Immune checkpoint inhibitors (ICIs) are effective in the treatment of patients with advanced cancer and have emerged as a pillar of standard cancer care. However, their use is complicated by adverse effects known as immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis. ICI-induced inflammatory arthritis is distinguished from other irAEs by its persistence and requirement for long-term treatment. TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis, spondyloarthropathies and inflammatory bowel disease, and have also been adopted as second-line agents to treat irAEs refractory to glucocorticoid treatment. Experiencing an irAE is associated with a better antitumour response after ICI treatment. However, whether TNF inhibition can be safely used to treat irAEs without promoting cancer progression, either by compromising ICI therapy efficacy or via another route, remains an open question. In this Review, we discuss clinical and preclinical studies that address the relationship between TNF, TNF inhibition and cancer. The bulk of the evidence suggests that at least short courses of TNF inhibitors are safe for the treatment of irAEs in patients with cancer undergoing ICI therapy. Data from preclinical studies hint that TNF inhibition might augment the antitumour effect of ICI therapy while simultaneously ameliorating irAEs.
Different arms of the immune response are important for autoimmune versus anticancer activities, and TNF inhibitors restrain some of these arms while promoting or having a neutral effect on others.
Preclinical studies provide evidence that short courses of TNF inhibitors, despite their efficacy in ameliorating immune-related adverse events (irAEs), do not restrain the anticancer effects of immune checkpoint inhibitors (ICIs).
TNF inhibitor treatment of rheumatic diseases does not seem to increase the risk of cancer, except for non-melanoma skin cancer and possibly lymphoma.
Short courses of TNF inhibitors are likely to be safe in the treatment of ICI-associated irAEs, but data on the safety of long-term TNF inhibitor use for irAEs are lacking.
Clinical studies that directly assess the effect of TNF inhibitor treatment on ICI efficacy are required to draw conclusions regarding the safety of TNF inhibitor treatment for irAEs.
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Arnaud-Coffin, P. et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int. J. Cancer 145, 639–648 (2019).
Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).
Chan, K. K. & Bass, A. R. Autoimmune complications of immunotherapy: pathophysiology and management. BMJ 369, m736 (2020).
Larkin, J., Hodi, F. S. & Wolchok, J. D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270–1271 (2015).
Kostine, 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).
Cappelli, L. C. et al. Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin. Arthritis Rheum. 48, 553–557 (2018).
Ghosh, N. et al. Checkpoint inhibitor-associated arthritis: a systematic review of case reports and case series. J. Clin. Rheumatol. https://doi.org/10.1097/RHU.0000000000001370 (2020).
Thompson, J. A. et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020: featured Updates to the NCCN Guidelines. J. Natl Compr. Cancer Netw. 18, 230–241 (2020).
Smith, M. H. & Bass, A. R. Arthritis after cancer immunotherapy: symptom duration and treatment response. Arthritis Care Res. 71, 362–366 (2019).
Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2019).
Kim, S. T. et al. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann. Rheum. Dis. 76, 2061–2064 (2017).
Roberts, J. et al. Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis. Clin. Rheumatol. 38, 1513–1519 (2019).
Teulings, H. E. et al. Vitiligo-like depigmentation in patients with stage III–IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J. Clin. Oncol. 33, 773–781 (2015).
Zhou, X. et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med. 18, 87 (2020).
Haratani, K. et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 4, 374–378 (2018).
Horvat, T. Z. et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J. Clin. Oncol. 33, 3193–3198 (2015).
Mahmood, S. S. et al. Myocarditis in patients treated with immune checkpoint inhibitors. J. Am. Coll. Cardiol. 71, 1755–1764 (2018).
Marthey, L. et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J. Crohns Colitis 10, 395–401 (2016).
Faje, A. T. et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 124, 3706–3714 (2018).
Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).
Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).
Nauts, H. C., Swift, W. E. & Coley, B. L. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res. 6, 205–216 (1946).
Shear, M. J. & Perrault, A. Chemical treatment of tumors. IX. Reactions of mice with primary subcutaneous tumors to injection of a hemorrhage-producing bacterial polysaccharide. J. Natl Cancer Inst. 4, 461–476 (1944).
O’Malley, W. E., Achinstein, B. & Shear, M. J. Journal of the National Cancer Institute, Vol. 29, 1962: Action of bacterial polysaccharide on tumors. II. Damage of sarcoma 37 by serum of mice treated with Serratia marcescens polysaccharide, and induced tolerance. Nutr. Rev. 46, 389–391 (1988).
Pennica, D. et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312, 724–729 (1984).
Fransen, L. et al. Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression. Nucleic Acids Res. 13, 4417–4429 (1985).
Beutler, B. et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316, 552–554 (1985).
Brennan, F. M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).
Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).
Gamm, H., Lindemann, A., Mertelsmann, R. & Herrmann, F. Phase I trial of recombinant human tumour necrosis factor α in patients with advanced malignancy. Eur. J. Cancer 27, 856–863 (1991).
Arican, O., Aral, M., Sasmaz, S. & Ciragil, P. Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 2005, 273–279 (2005).
Waters, J. P., Pober, J. S. & Bradley, J. R. Tumour necrosis factor and cancer. J. Pathol. 230, 241–248 (2013).
Robaye, B., Mosselmans, R., Fiers, W., Dumont, J. E. & Galand, P. Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro. Am. J. Pathol. 138, 447–453 (1991).
Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer 9, 361–371 (2009).
Wu, H., Tschopp, J. & Lin, S. C. Smac mimetics and TNFα: a dangerous liaison? Cell 131, 655–658 (2007).
Ratner, A. & Clark, W. R. Role of TNF-α in CD8+ cytotoxic T lymphocyte-mediated lysis. J. Immunol. 150, 4303–4314 (1993).
Caron, G. et al. Human NK cells constitutively express membrane TNF-α (mTNFα) and present mTNFα-dependent cytotoxic activity. Eur. J. Immunol. 29, 3588–3595 (1999).
Freedman, M. H. et al. Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia. Br. J. Haematol. 80, 40–48 (1992).
Fràter-Schroder, M., Risau, W., Hallmann, R., Gautschi, P. & Böhlen, P. Tumor necrosis factor type α, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc. Natl Acad. Sci. USA 84, 5277–5281 (1987).
Li, B. et al. Low levels of tumor necrosis factor α increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res. 69, 338–348 (2009).
Moore, R. J. et al. Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis. Nat. Med. 5, 828–831 (1999).
Starcher, B. Role for tumour necrosis factor-α receptors in ultraviolet-induced skin tumours. Br. J. Dermatol. 142, 1140–1147 (2000).
Karabela, S. P. et al. Neutralization of tumor necrosis factor bioactivity ameliorates urethane-induced pulmonary oncogenesis in mice. Neoplasia 13, 1143–1151 (2011).
Popivanova, B. K. et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).
Senthilkumar, C., Niranjali, S., Jayanthi, V., Ramesh, T. & Devaraj, H. Molecular and histological evaluation of tumor necrosis factor-α expression in Helicobacter pylori-mediated gastric carcinogenesis. J. Cancer Res. Clin. Oncol. 137, 577–583 (2011).
Suganuma, M., Kuzuhara, T., Yamaguchi, K. & Fujiki, H. Carcinogenic role of tumor necrosis factor-α inducing protein of Helicobacter pylori in human stomach. J. Biochem. Mol. Biol. 39, 1–8 (2006).
Wilson, A. G., Symons, J. A., McDowell, T. L., McDevitt, H. O. & Duff, G. W. Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proc. Natl Acad. Sci. USA 94, 3195–3199 (1997).
Louis, E. et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-α production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin. Exp. Immunol. 113, 401–406 (1998).
Guo, X. F. et al. TNF-α-308 polymorphism and risk of digestive system cancers: a meta-analysis. World J. Gastroenterol. 19, 9461–9471 (2013).
Ma, L. et al. Association between Tumor necrosis factor-alpha gene polymorphisms and prostate cancer risk: a meta-analysis. Diagn. Pathol. 9, 74 (2014).
Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).
Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).
Bradley, J. R. TNF-mediated inflammatory disease. J. Pathol. 214, 149–160 (2008).
Kalliolias, G. D. & Ivashkiv, L. B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49–62 (2016).
Apostolaki, M., Armaka, M., Victoratos, P. & Kollias, G. Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr. Dir. Autoimmun. 11, 1–26 (2010).
Gordon, C., Ranges, G. E., Greenspan, J. S. & Wofsy, D. Chronic therapy with recombinant tumor necrosis factor-α in autoimmune NZB/NZW F1 mice. Clin. Immunol. Immunopathol. 52, 421–434 (1989).
Jacob, C. O., Aiso, S., Michie, S. A., McDevitt, H. O. & Acha-Orbea, H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-α and interleukin 1. Proc. Natl Acad. Sci. USA 87, 968–972 (1990).
Cope, A. P. et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J. Exp. Med. 185, 1573–1584 (1997).
Chu, C. Q., Field, M., Feldmann, M. & Maini, R. N. Localization of tumor necrosis factor α in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).
Alsalameh, S. et al. Distribution of TNF-α, TNF-R55 and TNF-R75 in the rheumatoid synovial membrane: TNF receptors are localized preferentially in the lining layer; TNF-α is distributed mainly in the vicinity of TNF receptors in the deeper layers. Scand. J. Immunol. 49, 278–285 (1999).
Kunisch, E. et al. Predominant activation of MAP kinases and pro-destructive/pro-inflammatory features by TNF α in early-passage synovial fibroblasts via TNF receptor-1: failure of p38 inhibition to suppress matrix metalloproteinase-1 in rheumatoid arthritis. Ann. Rheum. Dis. 66, 1043–1051 (2007).
Notley, C. A. et al. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J. Exp. Med. 205, 2491–2497 (2008).
Hull, D. N. et al. Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis. Arthritis Res. Ther. 18, 303 (2016).
Taylor, P. C. et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38–47 (2000).
Koelink, P. J. et al. Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling. Gut 69, 1053–1063 (2020).
Housley, W. J. et al. Natural but not inducible regulatory T cells require TNF-α signaling for in vivo function. J. Immunol. 186, 6779–6787 (2011).
Punit, S. et al. Tumor necrosis factor receptor 2 restricts the pathogenicity of CD8+ T cells in mice with colitis. Gastroenterology 149, 993–1005.e2 (2015).
Chen, X. et al. TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis. Sci. Rep. 6, 32834 (2016).
Murray-Brown, W. et al. Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy. J. Immunother. Cancer 8, e000281 (2020).
Luoma, A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655–671.e22 (2020).
Lesage, C. et al. Incidence and clinical impact of anti-TNFα treatment of severe immune checkpoint inhibitor-induced colitis in advanced melanoma: the mecolit survey. J. Immunother. 42, 175–179 (2019).
Wang, Y. et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J. Immunother. Cancer 6, 37 (2018).
Verheijden, R. J. et al. Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1 treated patients in the Dutch Melanoma Treatment Registry. Clin. Cancer Res. 26, 2268–2274 (2020).
Weber, J. S. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35, 785–792 (2017).
Sznol, M. et al. Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma. J. Clin. Oncol. 35, 3815–3822 (2017).
Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018).
Eggermont, A. M. M. et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol. 6, 519–527 (2020).
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
Bridge, J. A., Lee, J. C., Daud, A., Wells, J. W. & Bluestone, J. A. Cytokines, chemokines, and other biomarkers of response for checkpoint inhibitor therapy in skin cancer. Front. Med. 5, 351 (2018).
Gibney, G. T., Weiner, L. M. & Atkins, M. B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17, e542–e551 (2016).
Baecklund, E., Smedby, K. E., Sutton, L. A., Askling, J. & Rosenquist, R. Lymphoma development in patients with autoimmune and inflammatory disorders–what are the driving forces? Semin. Cancer Biol. 24, 61–70 (2014).
Smitten, A. L., Simon, T. A., Hochberg, M. C. & Suissa, S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res. Ther. 10, R45 (2008).
Pouplard, C. et al. Risk of cancer in psoriasis: a systematic review and meta-analysis of epidemiological studies. J. Eur. Acad. Dermatol. Venereol. 27 (Suppl. 3), 36–46 (2013).
Deepak, P. et al. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-α (TNF-α) inhibitors: results of the REFURBISH study. Am. J. Gastroenterol. 108, 99–105 (2013).
Solomon, D. H. et al. Adverse effects of low-dose methotrexate: a randomized trial. Ann. Intern. Med. 172, 369–380 (2020).
Solomon, D. H., Mercer, E. & Kavanaugh, A. Observational studies on the risk of cancer associated with tumor necrosis factor inhibitors in rheumatoid arthritis: a review of their methodologies and results. Arthritis Rheum. 64, 21–32 (2012).
Askling, J. et al. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish biologics register. Ann. Rheum. Dis. 68, 648–653 (2009).
Nyboe Andersen, N. et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 311, 2406–2413 (2014).
Haynes, K. et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 65, 48–58 (2013).
de La Forest Divonne, M., Gottenberg, J. E. & Salliot, C. Safety of biologic DMARDs in RA patients in real life: a systematic literature review and meta-analyses of biologic registers. Joint Bone Spine 84, 133–140 (2017).
Hellgren, K. et al. Risk of solid cancers overall and by subtypes in patients with psoriatic arthritis treated with TNF inhibitors — a Nordic cohort study. Rheumatology https://doi.org/10.1093/rheumatology/keaa828 (2021).
Bongartz, T. et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295, 2275–2285 (2006).
Dixon, W. & Silman, A. Is there an association between anti-TNF monoclonal antibody therapy in rheumatoid arthritis and risk of malignancy and serious infection? Commentary on the meta-analysis by Bongartz et al. Arthritis Res. Ther. 8, 111 (2006).
Dommasch, E. D. et al. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. J. Am. Acad. Dermatol. 64, 1035–1050 (2011).
Lichtenstein, G. R. et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am. J. Gastroenterol. 107, 1051–1063 (2012).
Maneiro, J. R., Souto, A. & Gomez-Reino, J. J. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: systematic review, meta-analysis, and network meta-analysis. Semin. Arthritis Rheum. 47, 149–156 (2017).
Hou, L. Q. et al. The comparative safety of TNF inhibitors in ankylosing spondylitis — a meta-analysis update of 14 randomized controlled trials. Clin. Rev. Allergy Immunol. 54, 234–243 (2018).
Beukelman, T. et al. Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors. Ann. Rheum. Dis. 77, 1012–1016 (2018).
Jung, S. M., Kwok, S. K., Ju, J. H., Park, Y. B. & Park, S. H. Risk of malignancy in patients with rheumatoid arthritis after anti-tumor necrosis factor therapy: results from Korean National Health Insurance claims data. Korean J. Intern. Med. 34, 669–677 (2019).
Silva, F. et al. Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener’s): long-term followup of a multicenter longitudinal cohort. Arthritis Rheum. 63, 2495–2503 (2011).
Diak, P. et al. Tumor necrosis factor α blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 62, 2517–2524 (2010).
FDA. FDA Drug Safety Communication: Safety Review update on reports of hepatosplenic T-cell lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine http://wayback.archive-it.org/7993/20170112031812/http:/www.fda.gov/Drugs/DrugSafety/ucm250913.htm (2011).
Lemaitre, M. et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA 318, 1679–1686 (2017).
Wolfe, F. & Michaud, K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum. 56, 1433–1439 (2007).
Hellgren, K. et al. Rheumatoid arthritis and risk of malignant lymphoma: is the risk still increased? Arthritis Rheumatol. 69, 700–708 (2017).
Mercer, L. K. et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann. Rheum. Dis. 76, 497–503 (2017).
Hyams, J. S. et al. Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease. Gastroenterology 152, 1901–1914.e1903 (2017).
Raaschou, P., Simard, J. F., Holmqvist, M., Askling, J. & Group, A. S. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ 346, f1939 (2013).
Mercer, L. K. et al. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers. Ann. Rheum. Dis. 76, 386–391 (2017).
Hellgren, K. et al. Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers. Ann. Rheum. Dis. 76, 105–111 (2017).
Lopez-Olivo, M. A. et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 308, 898–908 (2012).
Peleva, E. et al. Risk of cancer in patients with psoriasis on biological therapies: a systematic review. Br. J. Dermatol. 178, 103–113 (2018).
Wang, J. L. et al. Risk of non-melanoma skin cancer for rheumatoid arthritis patients receiving TNF antagonist: a systematic review and meta-analysis. Clin. Rheumatol. 39, 769–778 (2019).
Scott, F. I. et al. Risk of nonmelanoma skin cancer associated with the use of immunosuppressant and biologic agents in patients with a history of autoimmune disease and nonmelanoma skin cancer. JAMA Dermatol. 152, 164–172 (2016).
Raaschou, P., Söderling, J., Turesson, C. & Askling, J. Tumor necrosis factor inhibitors and cancer recurrence in swedish patients with rheumatoid arthritis: a nationwide population-based cohort study. Ann. Intern. Med. 169, 291–299 (2018).
Silva-Fernández, L. et al. The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. Rheumatology 55, 2033–2039 (2016).
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 e1117 (2017).
Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).
Zappasodi, R. et al. Non-conventional inhibitory CD4+Foxp3−PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 33, 1017–1032.e1017 (2018).
Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).
Ham, B., Fernandez, M. C., D’Costa, Z. & Brodt, P. The diverse roles of the TNF axis in cancer progression and metastasis. Trends Cancer Res. 11, 1–27 (2016).
Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007).
Zheng, L. et al. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377, 348–351 (1995).
Kim, E. Y., Teh, S. J., Yang, J., Chow, M. T. & Teh, H. S. TNFR2-deficient memory CD8 T cells provide superior protection against tumor cell growth. J. Immunol. 183, 6051–6057 (2009).
Bertrand, F. et al. Blocking tumor necrosis factor α enhances CD8 T-cell-dependent immunity in experimental melanoma. Cancer Res. 75, 2619–2628 (2015).
Zheng, Y. et al. TNF-α-induced Tim-3 expression marks the dysfunction of infiltrating natural killer cells in human esophageal cancer. J. Transl Med. 17, 165 (2019).
Ivagnes, A. et al. TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer. Oncoimmunology 7, e1386826 (2018).
Grinberg-Bleyer, Y. et al. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J. Clin. Invest. 120, 4558–4568 (2010).
Zanin-Zhorov, A. et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328, 372–376 (2010).
Zaragoza, B. et al. Suppressive activity of human regulatory T cells is maintained in the presence of TNF. Nat. Med. 22, 16–17 (2016).
Bilate, A. M. & Lafaille, J. J. Can TNF-α boost regulatory T cells? J. Clin. Invest. 120, 4190–4192 (2010).
Chen, X. et al. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J. Immunol. 180, 6467–6471 (2008).
Govindaraj, C. et al. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin. Immunol. 149, 97–110 (2013).
Chopra, M. et al. Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis. Carcinogenesis 34, 1296–1303 (2013).
Torrey, H. et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci. Signal. 10, eaaf8608 (2017).
Torrey, H. et al. Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sézary syndrome. Leukemia 33, 1206–1218 (2019).
Chen, X. et al. Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3− conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J. Immunol. 185, 174–182 (2010).
Charles, K. A. et al. The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J. Clin. Invest. 119, 3011–3023 (2009).
Nunez, S. et al. T helper type 17 cells contribute to anti-tumour immunity and promote the recruitment of T helper type 1 cells to the tumour. Immunology 139, 61–71 (2013).
Martin-Orozco, N. et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31, 787–798 (2009).
Zhao, X. et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J. Clin. Invest. 122, 4094–4104 (2012).
Sade-Feldman, M. et al. Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38, 541–554 (2013).
Ren, G. et al. CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα. Cell Stem Cell 11, 812–824 (2012).
Lim, S. O. et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell 30, 925–939 (2016).
Bertrand, F. et al. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat. Commun. 8, 2256 (2017).
Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
Kim, E. Y. & Teh, H. S. Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: a functional link to CD28. J. Immunol. 173, 4500–4509 (2004).
Calzascia, T. et al. TNF-α is critical for antitumor but not antiviral T cell immunity in mice. J. Clin. Invest. 117, 3833–3845 (2007).
Berard, F. et al. Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells. J. Exp. Med. 192, 1535–1544 (2000).
Maney, N. J., Reynolds, G., Krippner-Heidenreich, A. & Hilkens, C. M. U. Dendritic cell maturation and survival are differentially regulated by TNFR1 and TNFR2. J. Immunol. 193, 4914–4923 (2014).
Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019).
Castro, F., Cardoso, A. P., Goncalves, R. M., Serre, K. & Oliveira, M. J. Interferon-γ at the crossroads of tumor immune surveillance or evasion. Front. Immunol. 9, 847 (2018).
Koch, J., Steinle, A., Watzl, C. & Mandelboim, O. Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol. 34, 182–191 (2013).
Marzo, A. L. et al. Tumor-specific CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity. J. Immunol. 165, 6047–6055 (2000).
Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).
Dobrzanski, M. J. Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy. Front. Oncol. 3, 63 (2013).
Briscoe, D. M., Cotran, R. S. & Pober, J. S. Effects of tumor necrosis factor, lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule-1 in vivo. Correlation with CD3+ T cell infiltration. J. Immunol. 149, 2954–2960 (1992).
Li, M. O. & Flavell, R. A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).
Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).
Chanmee, T., Ontong, P., Konno, K. & Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 6, 1670–1690 (2014).
The work of J.D.W. is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. J.D.W. is also affiliated with: Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. The authors would like to thank L.B. Ivashkiv at the Hospital for Special Surgery for his comments on the manuscript.
J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Arsenal, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F Star, Imvaq, Kyowa Hakko Kirin, Merck, Neon Therapeutics, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax and Syntalogic, Takara Bio, Trieza and Truvax; receives research support from AstraZeneca, Bristol Myers Squibb and Sephora; and has equity in Adaptive Biotechnologies, Apricity, Arsenal, BeiGene, Imvaq, Linnaeus, Tizona Pharmaceuticals. The other authors declare no competing interests.
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Chen, A.Y., Wolchok, J.D. & Bass, A.R. TNF in the era of immune checkpoint inhibitors: friend or foe?. Nat Rev Rheumatol 17, 213–223 (2021). https://doi.org/10.1038/s41584-021-00584-4