Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)
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- Published online on: July 8, 2025 https://doi.org/10.3892/mmr.2025.13615
- Article Number: 250
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Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Cancer immunotherapy activates the immune system by targeting tumor antigens, enabling recognition and destruction of cancer cells (1). Immune checkpoint inhibitors (ICIs), particularly antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), have markedly improved outcomes in various types of cancer (2–6). CTLA-4 inhibits T cell activation by competing with CD28 for CD80/CD86 binding (7,8). Antibodies such as ipilimumab and tremelimumab block CTLA-4, enhancing anti-tumor immunity (9–12). PD-1, expressed on multiple immune cells, suppresses T cell function through PD-L1/PD-L2 binding (13–16). Blocking this pathway with agents such as nivolumab or pembrolizumab restores T cell activity and shows efficacy in melanoma, lung cancer and other malignancies (17–22).
Although ICIs represent a major breakthrough in cancer therapy (23,24), they are associated with a wide range of immune-related side effects that can affect almost every organ, may lead to treatment discontinuation and compromise overall therapeutic efficacy (25,26). Immune-related adverse events (irAEs) are common, with reports indicating they affect 90% of patients treated with anti-CTLA-4 and 70% of those treated with anti-PD-1/PD-L1 therapies (27). Anti-CTLA-4 therapy has been associated with a higher incidence of side effects compared to anti-PD-1 and PD-L1 treatments. Additionally, combination therapy showed a higher occurrence of adverse effects compared to monotherapy (28). ICI-related irAEs are unique to certain organs, such as skin, liver, colon, thyroid, muscle and lungs (29). According to a previous report, endocrine irAEs were observed in 9.89% of patients, GI toxicities such as diarrhea and colitis occurred to 8.4% of patients and hepatotoxicity occurred to 4.94% (30). Additional irAEs, including those affecting the joints, lungs, kidneys and central nervous system, were observed in 6.5, 5.1, 2.56 and 2.01% of patients, respectively (26,30). Ocular toxicity, cardiotoxicity and inflammation were some of the rare adverse events reported (30). They happened in 0.8, 0.73 and 0.54% of patients, respectively (30). Overall, rheumatologic manifestations, pneumonitis and gastrointestinal symptoms such as diarrhea and colitis were more prevalent than dermatologic adverse events.
Rheumatic irAEs include arthritis, myositis and vasculitis. The most prevalent clinical symptom is arthritis, ICI-induced inflammatory arthritis (ICI-induced IA) among them (31). The incidence of ICI-induced IA ranges from 1–7%. However, ICI-induced IA markedly effects overall quality of life and persists longer than other irAEs. It is frequently overlooked due to its lower severity compared to life-threatening events.
Currently, there is no standardized diagnostic and assessment criteria for ICI-induced IA. Moreover, consensus on optimal treatment strategies remains elusive and is the subject of continuing debate (32). For the initial therapy of ICI-induced IA, patients received either non-steroidal anti-inflammatory drugs (NSAIDs) or steroids (such as glucocorticoids) for cases with moderate inflammation (31,33). When patients show no improvement or become resistant to NSAIDs or steroids, TNF inhibitors (TNFi) and IL-6 receptor blockers are employed to manage ICI-induced inflammatory arthritis (34–37). Nevertheless, TNFi may also impair ICI-induced anti-tumor immunity (38). In addition to being beneficial in the treatment of ICI-induced IA, IL-6 inhibitors have also demonstrated anti-tumor effects (39,40). To provide more clinical insights on choosing biological agents, studies examining IL-6 signaling inhibition in patients with ICI-induced IA were reviewed.
ICI-induced IA
Certain irAEs, such as colitis and pneumonitis, can be fatal, whereas others, including IA, impair an individual's quality of life. IA frequently goes unnoticed, probably due to its minimal effect on death rates, diagnostic irregularities that might be overlooked by cancer specialists and the extensive range of classification options in the Common Terminology Criteria for Adverse Events grading system used in clinical studies (41). Nevertheless, the importance of early detection of IA is increasingly recognized as a result of the functional loss of patients, reports of the rapid progression of erosions and the continued presence of joint complaints (34,35,42,43). Determining the exact frequency of IA due to irAEs is difficult; nonetheless, up to 43% of patients in immunotherapy trials reported joint pain and it is estimated that 3.0–7.5% of those treated with ICIs develop IA (44–47). Given the number of patients who acquire IA and the increasing use of ICI therapy, it is necessary to conduct further assessment of long-term results. This is especially important in the context of improved survival with ICI treatment and prior findings indicating that symptoms can persist even after ICIs are discontinued (34,35,42,43).
ICI-induced IA may demonstrate resistance to standard therapies and the management of severe and treatment-resistant ICI-induced IA is a topic of debate. The best way to treat ICI-induced IA is to give prednisolone at a dose of 0.5–1.0 mg per kilogram per day. If the use of glucocorticoid alone does not lead to improvement in ICI-induced IA, it is advised to consider the use of a TNFi (32). The problem with this strategy is that it calls for giving high doses of glucocorticoids for a long time, which could lead to problems such as osteoporosis, diabetes, or infections (48). Additionally, TNFi has the potential to reduce the immune response to malignant tumors (38). Given these limitations, more effective methods to treat ICI-induced arthritis in patients with cancer are needed. Reports also indicate IL-6 receptor antagonists have shown efficacy in managing ICI-induced IA, aside from TNFi (36). Additionally, studies indicate that IL-6 promotes cancer development and progression, whereas blocking IL-6 hinders these processes (39,40). Increased concentrations of IL-6 and C-reactive protein (CRP, which has a strong association with IL-6) are linked to decreased survival in patients treated with ICIs (49–51). IL-6 receptor antagonists are considered to work by inhibiting Th17 cells. The reduction of IL-6 does not impede the activity of CD8+ T lymphocytes, which possess anti-tumor properties. Consequently, it is considered that IL-6 inhibition has a lesser impact on malignant tumors than ICIs (52,53). Notably, preclinical studies have demonstrated synergistic effects when combining IL-6 receptor inhibitors with anti-PD-L1 therapies (54). Collectively, these findings suggest that IL-6-targeted therapies represent a viable strategy for the treatment of ICI-induced IA.
The effect of IL-6 biologics on ICI-induced IA
IL-6 biological function
IL-6 was first identified as B-cell-stimulating factor 2 (BSF-2), secreted by peripheral blood mononuclear cells activated by mitogens or antigens (55). In 1986, the gene responsible for BSF-2 was successfully cloned (56). BSF-2 was later identified as the same as the hepatocyte-stimulating factor, the hybridoma growth factor and IFN-β2, which was found to have no antiviral properties (55). The molecule was subsequently renamed IL-6 (55). Human IL-6 consists of 184 amino acids, featuring two potential N-glycosylation sites and four cysteine residues (57). The fundamental protein weighs ~20 kDa and glycosylation increases the natural IL-6 size to between 21 and 26 kDa (57).
IL-6 is rapidly produced and triggers an immediate immune response in reaction to infections or tissue damage resulting from burns and traumas (58). IL-6 promotes the conversion of activated B lymphocytes into plasma cells responsible for generating antibodies and stimulates the proliferation of hybridoma and myeloma cells (59). IL-6 not only affects B cells, but also influences T cells by prompting the targeted transformation of immature CD4+ T cells into specialized subsets of effector T cells (60). IL-6, in conjunction with TGF-β, uniquely encourages the differentiation of naïve CD4+ T cells into Th17 cells while inhibiting the TGF-β-driven development of regulatory T cells (Tregs) (61,62). Th17 cells are critical for host defense against extracellular pathogens, but their expansion, driven by IL-6, may also contribute to the breakdown of immune tolerance and the development of autoimmune and inflammatory diseases (58). In fact, in various autoimmune disease models, inhibiting IL-6 during the initial activation phase prevents Th17 and/or Th1 cells from becoming the primary subsets over Tregs within antigen-specific effector T-cell groups (63). This additionally hinders the onset of autoimmune disorders, irrespective of the antigens employed for vaccination. Moreover, IL-6 promotes the formation of T follicular helper cells and the production of IL-21 (64), a key regulator of immunoglobulin synthesis.
IL-6 also exerts multiple pathogenic effects in chronic inflammatory diseases. IL-6 generated by bone marrow stromal cells triggers the receptor activator of NF-κB ligand, a key driver of osteoclast differentiation and activation. Consequently, this process results in bone resorption and osteoporosis (65). IL-6 promotes the production of VEGFs, thereby enhancing angiogenesis and increasing vascular permeability. These pathological features are commonly observed in both cancer and the inflamed synovial tissues of patients with rheumatoid arthritis (58).
Cell signaling pathway mediated by IL-6 and its receptors
Various cell types generate IL-6, which plays a vital role in regulating the acute phase response, inflammation, hematopoiesis, liver regeneration, metabolism, bone remodeling and cancer progression (66). Classic IL-6 signaling is initiated when IL-6 binds to membrane-bound IL-6 receptor (IL-6R), forming a complex that associates with the signal-transducing subunit gp130 (67). The interaction of gp130 with the IL-6/IL-6R complex promotes the formation of gp130 dimers and leads to the assembly of a heterohexameric structure consisting of IL-6, IL-6R and gp130 in a 2:2:2 ratio (58). Traditional IL-6 signaling is largely limited to liver cells, immune cells such as macrophages and neutrophils, as well as inactive lymphocytes, because it requires the presence of membrane-bound IL-6R (68). Nonetheless, IL-6 can also trigger trans-signaling in cells that have gp130 but lack IL-6R. This mechanism includes IL-6 binding to a soluble form of IL-6R, which can be generated through either alternative splicing or proteolytic cleavage (58). The IL-6/soluble IL-6R complex can trigger IL-6 signaling mechanisms in cells that have gp130. Since gp130 is present in all tissues (69), trans-signaling enables a broader array of cells to react to IL-6. Activation of the IL-6 classic or trans-signaling ligand-receptor complexes triggers three intracellular signaling cascades: JAK-STAT, PI3K-Akt and Ras-MAPK pathways (70,71). The Ras-MAPK signaling network also includes the p38 MAPK, JNK MAPK and MEK-ERK5 pathways (see Fig. 1). Then, IL-6/IL-6R signaling regulates downstream gene expression and inflammatory responses by activating these downstream intracellular signaling pathways. IL-6R is primarily found on liver cells and immune cells, restricting the specific targets of IL-6 classic signaling. The IL-6 classic signaling route initiates the acute-phase response and is associated with homeostatic and anti-inflammatory effects (72). In contrast, trans-signaling, due to the widespread expression of gp130, enables IL-6 to exert pro-inflammatory effects in a broad range of tissues (73).
The effect of IL-6 on cancer development
IL-6 is often overexpressed in various types of cancer, both at the local tumor site and systemically (74). Elevated serum IL-6 levels are associated with poor prognosis and decreased survival rates in patients with cancer (75). Mechanistically, IL-6 has been reported to downregulate the expression of CDK2, CDK4 and CDK6, while upregulating the expression of p27Kip1 or p21WAF1/CIP1, thereby inducing G1 phase cell cycle arrest and contributing to the carcinogenesis of prostate cancer (76), hepatocellular carcinoma (77,78) and melanoma (79,80). Additionally, IL-6 supports the proliferation of multiple myeloma cells by modulating CDK4 and p16INK4A, affecting Rb phosphorylation and cell cycle progression (80). Upon binding to its receptor on malignant cells, IL-6 activates several pathways that promote tumor growth, such as JAK/STAT3, PI3K/AKT and Ras/MAPK, leading to enhanced cell survival, proliferation, invasion, migration and angiogenesis (81). It further promotes tumor invasion through upregulation of matrix metalloproteinases (MMPs), which degrade extracellular matrix components and facilitate metastasis (82,83). Within the tumor microenvironment, IL-6 stimulates stromal and endothelial cells to secrete chemokines and cytokines, which support tumor growth and neovascularization (84). Additionally, it fosters an immunosuppressive milieu, marked by recruiting Tregs, myeloid-derived suppressor cells and immunosuppressive M2 myeloid cells, which hinder robust anti-tumor immune reactions and aid in tumor immune escape (85). Furthermore, the IL-6/JAK2/STAT3 axis has been extensively studied in a wide range of malignancies, including liver, breast, colorectal, gastric and lung cancers, underscoring its role in tumorigenesis and its potential as a therapeutic target (86,87). Several IL-6-targeted strategies have shown efficacy in preclinical and clinical studies, including monoclonal antibodies against anti-IL-6/IL-6R or anti-sIL-6R, along with selective inhibitors targeting IL-6 downstream signaling pathways such as STAT3 or kinase inhibitors (such as JAK inhibitors) (81). Specifically, in medical research, treatments targeting IL-6 such as tocilizumab have proven effective in reducing cancer symptoms and preventing tumor growth (88). Clazakizumab (BMS945429, ALD518), a humanized monoclonal antibody targeting IL-6, has demonstrated good tolerability and alleviates anemia and cachexia associated with non-small cell lung cancer in both preclinical and Phase I/II trials (89). Overall, the strategy of targeting IL-6 signaling represents a promising strategy for cancer therapy.
IL-6 biologics in ICI-induced IA
IA is among the most commonly observed irAEs in patients receiving ICIs therapy. Anti-IL-6 biologic agents have been recommended as a therapeutic option for ICI-induced IA in the current irAEs treatment guidelines. In fact, IL-6 is crucial for the differentiation of naïve CD4+ T cells into Th17 cells, which are implicated in the pathogenesis of multiple autoimmune diseases and may also contribute to irAEs (52). At present, addressing irAEs, including ICI-induced IA, can be effectively managed with anti-IL-6R therapies, which does not compromise antitumor immunity (90). Various therapeutics for ICI-induced IA by blocking IL-6 signaling were discussed below (Fig. 2).
IL-6 direct inhibitors
According to previous reports, five IL-6 inhibitors are used to treat cancer and rheumatoid arthritis (RA) patients. These include Siltuximab (CNTO 328, Sylvant), Sirukumab (CNTO 136), Olokizumab (CP6038), mAb 1339 (OP-R003) and Clazakizumab (BMS945429, ALD518). However, none of them have been evaluated for treatment of ICI-induced IA.
IL-6R direct inhibitors
Tocilizumab (RoActemra or Actemra)Tocilizumab, a humanized monoclonal antibody targeting the IL-6R, blocks both soluble (sIL-6R) and membrane-bound (mIL-6R) forms of the receptor. It has been approved by the US Food and Drug Administration (FDA) for the treatment of RA (91). Tocilizumab's anti-cancer properties have been shown in multiple forms of cancer, such as a colon cancer xenograft model (92), kidney cancer (93), lung carcinoma (88) and breast malignancy (94). Tocilizumab is thus a feasible therapy option for ICI-induced IA. Holmstroem et al (95) demonstrated that 84% of patients treated with tocilizumab (8 mg/kg, up to 800 mg) every four weeks for a minimum of two cycles achieved complete remission of ICI-induced IA symptoms. Tocilizumab was shown to have favorable clinical effectiveness and a controllable safety profile when used to treat ICI-induced IA (95–102). Kim et al (36) noted that three individuals, who experienced severe arthritis during ICI treatment and received tocilizumab, showed marked clinical progress; one individual sustained a lasting anti-tumor response from checkpoint inhibition. Following methotrexate failure, five patients received tocilizumab, resulting in a 100% clinical response rate (103,104). Taken together, tocilizumab efficiently reduced symptoms of ICI-induced IA in patients with cancer (Table I).
Sarilumab (SAR153191 or REGN88)
Sarilumab (KEVZARA®), a human anti-IL-6R, was approved by FDA to treat RA on 22 May 2017 (91). Sarilumab has been reported to be effective in the treatment of ICI-induced polyarthritis (37). A 61-year-old renal cell carcinoma patient received biweekly subcutaneous injections of 200 mg sarilumab following failed prednisolone and sulfasalazine treatment (37). As a result, no recurrence of renal cell carcinoma was observed for 2 years following sarilumab beginning, despite no anti-tumor treatment (37). Hence, sarilumab may represent a promising therapeutic option for ICI-induced polyarthritis that is refractory to conventional treatments.
Gp130 direct inhibitors
The soluble gp130-Fc fusion protein (sgp130Fc or FE 999301), anti-gp130 monoclonal antibodies and small molecule inhibitors such as madindoline A, SC144, bazedoxifene, Raloxifene and LMT-28, have demonstrated the ability to inhibit IL-6/JAK/STAT3 signaling. However, most of these treatments require further evaluation in preclinical and clinical settings, particularly in the context of ICI-induced IA.
JAK inhibitors
Research has shown that JAK inhibitors such as TG101209, CEP 3379, WP1066, sorafenib and AG490 are effective against various types of cancer (105). Nevertheless, none of these agents has been reported to be effective in treating ICI-induced IA. Ruxolitinib, another JAK inhibitor, has shown clinical efficacy in managing ICI-induced myocarditis (106), but its therapeutic potential in ICI-induced IA remains to be determined. Overall, the role of JAK inhibitors in the management of ICI-induced IA is not well established and warrants further investigation.
STAT3 inhibitors
STAT3 inhibitors offer an alternative therapeutic strategy aimed at blocking IL-6/JAK/STAT3 signaling through the prevention of STAT3 phosphorylation. For example, JSI-124 has been shown to suppress tumor growth and progression (107). S3I-201, which is also referred to as NSC74859, binds to the DNA-binding domain of STAT3, thereby inhibiting the proliferation and survival of human breast cancer cells (108). Nonetheless, the efficacy of STAT3 blockers in managing ICI-triggered IA remains largely unclear, necessitating additional studies to clarify this matter.
The underlying mechanism for treating ICI-induced IA by IL-6 signaling inhibitors
Blocking IL-6 signaling reinstates T cell suppression through the PD-1/PD-L1 pathwayImmune checkpoint blockers, including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, lead to immune-related side effects. This is due to the fact that PD-1, PD-L1 and CTLA-4 are found not only in tumor cells but also in various other tissue cells (109). Dysregulation of these immune checkpoints has been strongly linked to the inflammatory responses. A previous study indicated that PD-1 knockout mice develop more severe arthritis, whereas PD-L1 Fc therapy was shown to prevent collagen-induced arthritis (110). Additionally, PD-1 gene variations have been linked to a higher likelihood of rheumatic arthritis (111). IL-6 counteracts the suppression of T cells mediated by PD-1/PD-L1. The introduction of the anti-IL-6 receptor antibody tocilizumab mitigates IL-6-driven inflammation and restores PD-L1-mediated T cell suppression (112). Therefore, biologic agents targeting IL-6, which effectively treat ICI-induced IA, might work by reinstating T cell suppression via the PD-1/PD-L1 pathway in the synovial tissue (Fig. 2). Conversely, reports indicate that anti-IL-6 biological agents can enhance the anti-cancer efficacy of ICIs by improving the tumor-fighting abilities of cytotoxic T cells (113). Further underlying molecular mechanism is still required to be investigated. Overall, it seems plausible that the fundamental process behind using anti-IL-6 biologic medications to address ICI-induced IA involves restoring T cell suppression in target tissues through the PD-1/PD-L1 pathway.
Targeting IL-6 signaling suppresses Th17/B cell differentiation
The symptoms of irAEs frequently indicated a widespread inflammatory reaction, evidenced by a significant increase in CRP levels. CRP, a downstream marker of IL-6 signaling, shows an elevation from baseline levels during the initial occurrence of irAE (114). The rise in circulating IL-6 is considered to result from T-cell activation triggered by ICIs (115,116). High concentrations of IL-6 in the bloodstream cause pro-inflammatory responses via trans-signaling. IL-6 attaches to a sIL-6R, thereby triggering a broader spectrum of cells than traditional signaling (117). Classic IL-6 signaling occurs under low IL-6 concentrations and is restricted to cells expressing IL-6R, such as Th17 cells in specific tissues (118). Increased IL-6 levels have been observed in the tissues of irAEs among two distinct cohorts of 23 patients with solid tumors treated with anti-CTLA-4 and/or anti-PD-1 therapies (119). This increase was associated with a boost in the expression of genes tied to Th17 cells, leading to a greater percentage of Th17 cells within the total T cell population in tissues, thereby contributing to the pathogenesis of irAEs (119). Tocilizumab, an IL-6 inhibitor, has been shown to suppress the differentiation of naïve CD4+ T cells into Th17 cells within synovial tissue (120). Moreover, Th17 cells further promote B cell differentiation into plasma cells that produce anti-citrullinated protein antibodies and rheumatoid factor within the synovial tissue (121,122). Therefore, blockade of IL-6 inhibited the development of ICI-induced IA by inhibiting Th17 and B cell differentiation (Fig. 2).
Conclusions
The interplay between IL-6 signaling and immune checkpoint inhibitor therapy highlights the delicate balance between maximizing anti-tumor efficacy and minimizing irAEs. While targeting IL-6 represents a promising strategy to mitigate irAEs, a more comprehensive understanding of its underlying mechanisms and interactions is crucial for developing safe and effective therapeutic approaches. Emerging evidence underscores the complex and context-dependent role of IL-6 in tumor progression and immune modulation, suggesting that IL-6 signaling is not only a contributor to cancer pathogenesis but also a potential therapeutic target. Future research should aim to elucidate the multifaceted roles of IL-6 in oncogenesis and immunotherapy and to design more selective inhibitors that effectively modulate IL-6 pathways or their downstream effects. Such advancements could pave the way for personalized treatment strategies and ultimately improve clinical outcomes for patients with cancer with elevated IL-6 activity.
Acknowledgements
Not applicable.
Funding
The present study was supported by National Natural Science Foundation of China (grant nos. 82100557 and 82271256).
Availability of data and materials
Not applicable.
Authors' contributions
TH, LZ, YG and CF drafted the manuscript. TH and YG prepared the figures and table. Data authentication is not applicable. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Authors' information
Tianzhen He ORCID: 0000-0001-7873-853X. Yong-Jing Gao ORCID: 0000-0002-7432-7458
References
|
Zang X: 2018 nobel prize in medicine awarded to cancer immunotherapy: Immune checkpoint blockade-A personal account. Genes Dis. 5:302–303. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xie R, Shang B, Bi X, Cao C, Guan Y, Shi H and Shou J: Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta-analysis. Cancer Innov. 1:293–304. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Seidel JA, Otsuka A and Kabashima K: Anti-PD-1 and Anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations. Front Oncol. 8:862018. View Article : Google Scholar | |
|
Li H, Yuan S, Wu H, Wang Y, Ma Y, Tang X, Fu X, Zhao L, Xu B, Li T, et al: Combination therapy using low-dose anlotinib and immune checkpoint inhibitors for extensive-stage small cell lung cancer. Cancer Innov. 3:e1552024. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao J, Zhuo X, Liu L, Yang Z and Fu G: Opportunities and challenges of immune checkpoint inhibitors for extensive-stage small-cell lung cancer. Cancer Innov. 1:183–193. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Mao L, Yang M, Fan X, Li W, Huang X, He W, Lin T and Huang J: PD-1/L1 inhibitors can improve but not replace chemotherapy for advanced urothelial carcinoma: A systematic review and network meta-analysis. Cancer Innov. 2:191–202. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Rudd CE, Taylor A and Schneider H: CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 229:12–26. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Rowshanravan B, Halliday N and Sansom DM: CTLA-4: A moving target in immunotherapy. Blood. 131:58–67. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kim GR and Choi JM: Current understanding of cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling in T-cell biology and disease therapy. Mol Cells. 45:513–521. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Babamohamadi M, Mohammadi N, Faryadi E, Haddadi M, Merati A, Ghobadinezhad F, Amirian R, Izadi Z and Hadjati J: Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy. Cell Death Dis. 15:172024. View Article : Google Scholar : PubMed/NCBI | |
|
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM and Reck M: Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 30:2046–2054. 2012. View Article : Google Scholar | |
|
Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA Jr, Donehower RC, Jaffee EM and Laheru DA: Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 36:382–389. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, Ladwa R, O'Byrne K and Kulasinghe A: Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 29:3044–3060. 2022. View Article : Google Scholar | |
|
Gutic B, Bozanovic T, Mandic A, Dugalic S, Todorovic J, Stanisavljevic D, Dugalic MG, Sengul D, Detanac DA, Sengul I, et al: Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy. Clinics (Sao Paulo). 78:1001772023. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Z, Zhang Y, Liu C, Shao J, Chen Y, Zhu Y, Zhang L, Qin B, Kong Z, Wang X, et al: A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer. Cancer Innov. 2:172–180. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Sun D, Xing P and Li J: PD-L1 blockade by immune checkpoint inhibitors impairs sensitivity to osimertinib in EGFR-mutant non-small cell lung cancer cells. Cancer Innov. 1:348–349. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L and Wang S: The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 13:9644422022. View Article : Google Scholar | |
|
Han Y, Liu D and Li L: PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res. 10:727–742. 2020.PubMed/NCBI | |
|
Ai L, Xu A and Xu J: Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol. 1248:33–59. 2020. View Article : Google Scholar | |
|
Topalian SL, Drake CG and Pardoll DM: Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 27:450–461. 2015. View Article : Google Scholar | |
|
Chikuma S: Basics of PD-1 in self-tolerance, infection, and cancer immunity. Int J Clin Oncol. 21:448–455. 2016. View Article : Google Scholar | |
|
Yi M, Zheng X, Niu M, Zhu S, Ge H and Wu K: Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol Cancer. 21:282022. View Article : Google Scholar : PubMed/NCBI | |
|
De Velasco MA, Kura Y, Fujita K and Uemura H: Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer. Int J Urol. 31:307–324. 2024. View Article : Google Scholar | |
|
Xue J, Liu C, Shao J, Wang L, Han Y and Wang J and Wang J: Predictive value of neutrophil-to-lymphocyte ratio for immune checkpoint inhibitor-related myocarditis among patients treated for non-small-cell lung cancer. Cancer Innov. 4:e1632025. View Article : Google Scholar : PubMed/NCBI | |
|
Postow MA, Sidlow R and Hellmann MD: Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 378:158–168. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Tucker L, Sacks S and Al-Mossawi H: THU0562 Inflammatory joint disease triggered by immune checkpoint inhibitors. Ann Rheum Dis. 76:4192017. View Article : Google Scholar | |
|
Lee DJ, Lee HJ Jr, Farmer JR and Reynolds KL: Mechanisms driving immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Curr Cardiol Rep. 23:982021. View Article : Google Scholar : PubMed/NCBI | |
|
Darnell EP, Mooradian MJ, Baruch EN, Yilmaz M and Reynolds KL: Immune-related adverse events (irAEs): Diagnosis, management, and clinical Pearls. Curr Oncol Rep. 22:392020. View Article : Google Scholar : PubMed/NCBI | |
|
Melia A, Fockens E, Sfumato P, Zemmour C, Madroszyk A, Lafforgue P and Pham T: Musculoskeletal immune-related adverse events in 927 patients treated with immune checkpoint inhibitors for solid cancer. Joint Bone Spine. 90:1054572023. View Article : Google Scholar : PubMed/NCBI | |
|
Thapa B, Roopkumar J, Kim AS, Gervaso L, Patil PD, Calabrese C, Khorana AA and Funchain P: Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI). J Clin Oncol. 37:e141512019. View Article : Google Scholar | |
|
Jeurling S and Cappelli LC: Treatment of immune checkpoint inhibitor-induced inflammatory arthritis. Curr Opin Rheumatol. 32:315–320. 2020. View Article : Google Scholar | |
|
Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J and Jordan K; ESMO Guidelines Committee, : Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 28 (Suppl 4):iv119–iv142. 2017. View Article : Google Scholar | |
|
Chan KK and Bass AR: Monitoring and management of the patient with immune checkpoint inhibitor-induced inflammatory arthritis: Current perspectives. J Inflamm Res. 15:3105–3118. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Calabrese C, Kirchner E, Kontzias A, Velcheti V and Calabrese LH: Rheumatic immune-related adverse events of checkpoint therapy for cancer: Case series of a new nosological entity. RMD Open. 3:e0004122017. View Article : Google Scholar : PubMed/NCBI | |
|
Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, Lipson EJ, Bleich KB, Shah AA, Naidoo J, et al: Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 76:43–50. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Kim ST, Tayar J, Trinh VA, Suarez-Almazor M, Garcia S, Hwu P, Johnson DH, Uemura M and Diab A: Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: A case series. Ann Rheum Dis. 76:2061–2064. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Abe K, Ishikawa Y, Fujiwara M, Yukawa H, Yanagihara T, Takei S, Arioka H and Kita Y: Immune checkpoint inhibitor-induced refractory polyarthritis rapidly improved by sarilumab and monitoring with joint ultrasonography: A case report. Medicine (Baltimore). 101:e284282022. View Article : Google Scholar : PubMed/NCBI | |
|
Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford AR, Mak TW and Ohashi PS: TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest. 117:3833–3845. 2007. View Article : Google Scholar | |
|
Chang Q, Daly L and Bromberg J: The IL-6 feed-forward loop: A driver of tumorigenesis. Semin Immunol. 26:48–53. 2014. View Article : Google Scholar | |
|
Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T, Oike Y, Endo M, Ibusuki M, Hiraki A, et al: Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res. 15:5426–5434. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
U.S. Department of Health and Human Services, . Common terminology criteria for adverse events (CTCAE) version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5×7.pdfOctober 31–2019 | |
|
Albayda J, Dein E, Shah AA, Bingham CO III and Cappelli L: Sonographic findings in inflammatory arthritis secondary to immune checkpoint inhibition: A case series. ACR Open Rheumatol. 1:303–307. 2019. View Article : Google Scholar | |
|
Smith MH and Bass AR: Arthritis after cancer immunotherapy: Symptom duration and treatment response. Arthritis Care Res (Hoboken). 71:362–366. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Cappelli LC, Gutierrez AK, Bingham CO III and Shah AA: Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: A systematic review of the literature. Arthritis Care Res (Hoboken). 69:1751–1763. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C, Dousset L, Pham-Ledard A, Prey S, Beylot-Barry M, et al: Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: A single-centre prospective cohort study. Ann Rheum Dis. 77:393–398. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Buder-Bakhaya K, Benesova K, Schulz C, Anwar H, Dimitrakopoulou-Strauss A, Weber TF, Enk A, Lorenz HM and Hassel JC: Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies. Cancer Immunol Immunother. 67:175–182. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Lidar M, Giat E, Garelick D, Horowitz Y, Amital H, Steinberg-Silman Y, Schachter J, Shapira-Frommer R and Markel G: Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev. 17:284–289. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Huscher D, Thiele K, Gromnica-Ihle E, Hein G, Demary W, Dreher R, Zink A and Buttgereit F: Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis. 68:1119–1124. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Damuzzo V, Solito S, Pinton L, Carrozzo E, Valpione S, Pigozzo J, Giancristofaro RA, Chiarion-Sileni V and Mandruzzato S: Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab. Oncoimmunology. 5:e12495592016. View Article : Google Scholar : PubMed/NCBI | |
|
Tachibana H, Nemoto Y, Ishihara H, Fukuda H, Yoshida K, Iizuka J, Hashimoto Y, Kondo T, Tanabe K and Takagi T: Predictive impact of early changes in serum C-reactive protein levels in nivolumab plus ipilimumab therapy for metastatic renal cell carcinoma. Clin Genitourin Cancer. 20:e81–e88. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Shi Y, Liu X, Du J, Zhang D, Liu J, Chen M, Zhao J, Zhong W, Xu Y and Wang M: Circulating cytokines associated with clinical outcomes in advanced non-small cell lung cancer patients who received chemoimmunotherapy. Thorac Cancer. 13:219–227. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Diehl S and Rincón M: The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 39:531–536. 2002. View Article : Google Scholar | |
|
Vilgelm AE: Illuminating the mechanism of IL-6-mediated immunotherapy resistance. Cell Rep Med. 4:1009012023. View Article : Google Scholar : PubMed/NCBI | |
|
Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, Senju S, Ihn H, Nishimura Y and Oshiumi H: Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 78:5011–5022. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kishimoto T: The biology of interleukin-6. Blood. 74:1–10. 1989. View Article : Google Scholar : PubMed/NCBI | |
|
Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K and Iwamatsu A: Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 324:73–76. 1986. View Article : Google Scholar : PubMed/NCBI | |
|
Tanaka T and Kishimoto T: The biology and medical implications of interleukin-6. Cancer Immunol Res. 2:288–294. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Tanaka T, Narazaki M and Kishimoto T: IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 6:a0162952014. View Article : Google Scholar | |
|
Hirano T: IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 33:127–148. 2021. View Article : Google Scholar | |
|
Dienz O and Rincon M: The effects of IL-6 on CD4 T cell responses. Clin Immunol. 130:27–33. 2009. View Article : Google Scholar | |
|
Kimura A and Kishimoto T: IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 40:1830–1835. 2010. View Article : Google Scholar | |
|
Tanaka T, Narazaki M and Kishimoto T: Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 52:199–219. 2012. View Article : Google Scholar | |
|
Haruta H, Ohguro N, Fujimoto M, Hohki S, Terabe F, Serada S, Nomura S, Nishida K, Kishimoto T and Naka T: Blockade of interleukin-6 signaling suppresses not only Th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 52:3264–3271. 2011. View Article : Google Scholar | |
|
Ma CS, Deenick EK, Batten M and Tangye SG: The origins, function, and regulation of T follicular helper cells. J Exp Med. 209:1241–1253. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Feng W, Liu H, Luo T, Liu D, Du J, Sun J, Wang W, Han X, Yang K, Guo J, et al: Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways. Sci Rep. 7:414112017. View Article : Google Scholar : PubMed/NCBI | |
|
Akira S, Taga T and Kishimoto T: Interleukin-6 in biology and medicine. Adv Immunol. 54:1–78. 1993. View Article : Google Scholar | |
|
Rose-John S: Interleukin-6 signalling in health and disease. F1000Res. 9:F1000Faculty Rev. –1013. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Groza Y, Jemelkova J, Kafkova LR, Maly P and Raska M: IL-6 and its role in IgA nephropathy development. Cytokine Growth Factor Rev. 66:1–14. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Hunter CA and Jones SA: IL-6 as a keystone cytokine in health and disease. Nat Immunol. 16:448–457. 2015. View Article : Google Scholar | |
|
Wang J, Sun Q, Zhang J, Wang H and Liu H: Classical signaling and trans-signaling pathways stimulated by megalobrama amblycephala IL-6 and IL-6R. Int J Mol Sci. 23:20192022. View Article : Google Scholar | |
|
Schmidt-Arras D and Rose-John S: Endosomes as signaling platforms for IL-6 family cytokine receptors. Front Cell Dev Biol. 9:6883142021. View Article : Google Scholar | |
|
Rose-John S: IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 8:1237–1247. 2012. View Article : Google Scholar | |
|
Song M, Wang Y, Annex BH and Popel AS: Experiment-based computational model predicts that IL-6 classic and trans-signaling exhibit similar potency in inducing downstream signaling in endothelial cells. NPJ Syst Biol Appl. 9:452023. View Article : Google Scholar | |
|
Kozłowski L, Zakrzewska I, Tokajuk P and Wojtukiewicz MZ: Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst. 48:82–84. 2003. | |
|
Shibayama O, Yoshiuchi K, Inagaki M, Matsuoka Y, Yoshikawa E, Sugawara Y, Akechi T, Wada N, Imoto S, Murakami K, et al: Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy. Cancer Med. 3:702–709. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Mori S, Murakami-Mori K and Bonavida B: Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun. 257:609–614. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Klausen P, Pedersen L, Jurlander J and Baumann H: Oncostatin M and interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells. Oncogene. 19:3675–3683. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Moran DM, Mattocks MA, Cahill PA, Koniaris LG and McKillop IH: Interleukin-6 mediates G(0)/G(1) growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway. J Surg Res. 147:23–33. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Flørenes VA, Lu C, Bhattacharya N, Rak J, Sheehan C, Slingerland JM and Kerbel RS: Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. Oncogene. 18:1023–1032. 1999. View Article : Google Scholar | |
|
Kortylewski M, Heinrich PC, Mackiewicz A, Schniertshauer U, Klingmüller U, Nakajima K, Hirano T, Horn F and Behrmann I: Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. Oncogene. 18:3742–3753. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M and Jadidi-Niaragh F: The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 108:1415–1424. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Cathcart JM, Banach A, Liu A, Chen J, Goligorsky M and Cao J: Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression. Oncotarget. 7:61107–61120. 2016. View Article : Google Scholar | |
|
Chung YC, Chen SJ, Huang CC, Liu WC, Lai MT, Kao TY, Yang WS, Yang CH, Hsu CP and Chang JF: Tocilizumab exerts anti-tumor effects on colorectal carcinoma cell xenografts corresponding to expression levels of interleukin-6 receptor. Pharmaceuticals (Basel). 17:1272024. View Article : Google Scholar : PubMed/NCBI | |
|
Chonov DC, Ignatova MMK, Ananiev JR and Gulubova MV: IL-6 activities in the tumour microenvironment. Part 1. Open Access Maced J Med Sci. 7:2391–2398. 2019. View Article : Google Scholar | |
|
Fu C, Jiang L, Hao S, Liu Z, Ding S, Zhang W, Yang X and Li S: Activation of the IL-4/STAT6 signaling pathway promotes lung cancer progression by increasing M2 myeloid cells. Front Immunol. 10:26382019. View Article : Google Scholar | |
|
Huang B, Lang X and Li X: The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol. 12:10231772022. View Article : Google Scholar | |
|
Xu J, Lin H, Wu G, Zhu M and Li M: IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol. 11:7609712021. View Article : Google Scholar | |
|
Ando K, Takahashi F, Kato M, Kaneko N, Doi T, Ohe Y, Koizumi F, Nishio K and Takahashi K: Tocilizumab, a proposed therapy for the cachexia of interleukin6-expressing lung cancer. PLoS One. 9:e1024362014. View Article : Google Scholar : PubMed/NCBI | |
|
Bayliss TJ, Smith JT, Schuster M, Dragnev KH and Rigas JR: A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther. 11:1663–1668. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Fa'ak F, Buni M, Falohun A, Lu H, Song J, Johnson DH, Zobniw CM, Trinh VA, Awiwi MO, Tahon NH, et al: Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events. J Immunother Cancer. 11:e0068142023. View Article : Google Scholar | |
|
Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M and Yao Y: Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 141:125–139. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M and Takeyama H: Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 110:469–478. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Oguro T, Ishibashi K, Sugino T, Hashimoto K, Tomita S, Takahashi N, Yanagida T, Haga N, Aikawa K, Suzutani T, et al: Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression. Eur J Cancer. 49:1715–1724. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Wang D, Xu J, Liu B, He X, Zhou L, Hu X, Qiao F, Zhang A, Xu X, Zhang H, et al: IL6 blockade potentiates the anti-tumor effects of γ-secretase inhibitors in Notch3-expressing breast cancer. Cell Death Differ. 25:330–339. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Holmstroem RB, Nielsen OH, Jacobsen S, Riis LB, Theile S, Bjerrum JT, Vilmann P, Johansen JS, Boisen MK, Eefsen RHL, et al: COLAR: Open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis. J Immunother Cancer. 10:e0051112022. View Article : Google Scholar : PubMed/NCBI | |
|
Richter MD, Crowson C, Kottschade LA, Finnes HD, Markovic SN and Thanarajasingam U: Rheumatic syndromes associated with immune checkpoint inhibitors: A single-center cohort of sixty-one patients. Arthritis Rheumatol. 71:468–475. 2019. View Article : Google Scholar | |
|
Abdel-Wahab N, Shah M, Lopez-Olivo MA and Suarez-Almazor ME: Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: A systematic review. Ann Intern Med. 168:121–130. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Mooradian M, Fintelmann F, Fadden R, Rubin KM, Lawless A, Vitali M, Sharova T, Boland GM, Lawrence DP, Cohen JV, et al: A phase II study of cryoablation (cryo) of an enlarging tumor in patients (pts) with advanced lung cancer or melanoma receiving post-progression immune checkpoint inhibition (ICI). J Clin Oncol. 37:e14243. 2019. View Article : Google Scholar | |
|
Verspohl SH, Holderried T, Behning C, Brossart P and Schäfer VS: Prevalence, therapy and tumour response in patients with rheumatic immune-related adverse events following immune checkpoint inhibitor therapy: A single-centre analysis. Ther Adv Musculoskelet Dis. 13:1759720×2110069632021. View Article : Google Scholar | |
|
Ladouceur A, Barnetche T, Mouterde G, Tison A, Bitoun S, Prey S, Dutriaux C, Gerard E, Pham-Ledard A, Beylot-Barry M, et al: Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: A multicentre observational study. RMD Open. 9:e0037952023. View Article : Google Scholar : PubMed/NCBI | |
|
Pirker I, Rubbert-Roth A, von Kempis J, Fehr M and Neumann T: Tocilizumab in a patient with newly diagnosed rheumatoid arthritis secondary to checkpoint inhibitor therapy. Clin Exp Rheumatol. 38:573–574. 2020. | |
|
Mooradian MJ, Nasrallah M, Gainor JF, Reynolds KL, Cohen JV, Lawrence DP, Miloslavsky EM, Kohler MJ, Sullivan RJ and Schoenfeld SR: Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: A single center experience. Semin Arthritis Rheum. 48:1127–1132. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Liapi M and Chatzidionysiou K: POS1356 treatment of immune checkpoint inhibitor-induced inflammatory arthritis and polymyalgia rheumatica. Ann Rheum Dis. 81:10172022. View Article : Google Scholar : PubMed/NCBI | |
|
Saygin C, Kishtagari A, Cassaday RD, Reizine N, Yurkiewicz I, Liedtke M, Stock W, Larson RA, Levine RL, Tallman MS, et al: Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes. Blood Adv. 3:4228–4237. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Hu X, Li J, Fu M, Zhao X and Wang W: The JAK/STAT signaling pathway: From bench to clinic. Signal Transduct Target Ther. 6:4022021. View Article : Google Scholar : PubMed/NCBI | |
|
Byer SH, Stewart C, Mansour S and Grewal US: Novel use of abatacept and ruxolitinib as salvage therapy in steroid-refractory immune checkpoint blockade-induced myocarditis with myasthenia and myositis overlap syndrome. Eur J Cancer. 202:1140272024. View Article : Google Scholar : PubMed/NCBI | |
|
Schust J, Sperl B, Hollis A, Mayer TU and Berg T: Stattic: A small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 13:1235–1242. 2006. View Article : Google Scholar | |
|
Yue P and Turkson J: Targeting STAT3 in cancer: How successful are we? Expert Opin Investig Drugs. 18:45–56. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Qin W, Hu L, Zhang X, Jiang S, Li J, Zhang Z and Wang X: The diverse function of PD-1/PD-l pathway beyond cancer. Front Immunol. 10:22982019. View Article : Google Scholar | |
|
Raptopoulou AP, Bertsias G, Makrygiannakis D, Verginis P, Kritikos I, Tzardi M, Klareskog L, Catrina AI, Sidiropoulos P and Boumpas DT: The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis Rheum. 62:1870–1880. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Kong EKP, Prokunina-Olsson L, Wong WHS, Lau CS, Chan TM, Alarcón-Riquelme M and Lau YL: A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum. 52:1058–1062. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Bommarito D, Hall C, Taams LS and Corrigall VM: Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1. Clin Exp Immunol. 188:455–466. 2017. View Article : Google Scholar | |
|
Huseni MA, Wang L, Klementowicz JE, Yuen K, Breart B, Orr C, Liu LF, Li Y, Gupta V, Li C, et al: CD8+T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy. Cell Rep Med. 4:1008782023. View Article : Google Scholar : PubMed/NCBI | |
|
Yu Y, Wang S, Su N, Pan S, Tu B, Zhao J, Shen Y, Qiu Q, Liu X, Luan J, et al: Increased circulating levels of CRP and IL-6 and decreased frequencies of T and B lymphocyte subsets are associated with immune-related adverse events during combination therapy with PD-1 inhibitors for liver cancer. Front Oncol. 12:9068242022. View Article : Google Scholar | |
|
McArthur GA and Ribas A: Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 31:499–506. 2013. View Article : Google Scholar | |
|
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B and von Bergwelt-Baildon MS: Cytokine release syndrome. J Immunother Cancer. 6:562018. View Article : Google Scholar : PubMed/NCBI | |
|
Baran P, Hansen S, Waetzig GH, Akbarzadeh M, Lamertz L, Huber HJ, Ahmadian MR, Moll JM and Scheller J: The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem. 293:6762–6775. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA and Mackall CL: Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 124:188–195. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Hailemichael Y, Johnson DH, Abdel-Wahab N, Foo WC, Bentebibel SE, Daher M, Haymaker C, Wani K, Saberian C, Ogata D, et al: Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 40:509–523.e506. 2022. View Article : Google Scholar | |
|
Mihara M, Ohsugi Y and Kishimoto T: Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis. Open Access Rheumatol. 3:19–29. 2011. View Article : Google Scholar | |
|
Bystrom J, Taher TE, Henson SM, Gould DJ and Mageed RA: Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases. Front Immunol. 13:9907942022. View Article : Google Scholar | |
|
Wu F, Gao J, Kang J, Wang X, Niu Q, Liu J and Zhang L: B cells in rheumatoid arthritis: Pathogenic mechanisms and treatment prospects. Front Immunol. 12:7507532021. View Article : Google Scholar |
