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      Management of rheumatic complications of immune checkpoint inhibitor therapy – an oncological perspective

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          Abstract

          Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control.

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          Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy.

          Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab) and three PD-L1 blockers (atezolizumab, avelumab and durvalumab) are approved for the treatment of different types of cancers including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder cancer and Merkel cell cancer as well as hematological tumors such as classic Hodgkin's lymphoma. The main problem with checkpoint blockers is that only a fraction of patients respond to the therapy. Insufficient immune activation is considered as one of the main reason for low response rates and combination of checkpoint blockers has been proposed to increase the response rates. The combination of checkpoint blockers was successful in melanoma but had significant adverse events. A combination that is selected based on the mechanistic differences between checkpoints and the differences in expression of checkpoints and their ligands in the tumor microenvironment could have a synergistic effect in a given cancer subtype and also have a manageable safety profile. This review aims to help in design of optimal checkpoint blocker combinations by discussing the mechanistic details and outlining the subtle differences between major checkpoints targeted for cancer immunotherapy.
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            TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma

            Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.
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              Tumor immune evasion arises through loss of TNF sensitivity

              Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)–based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8+ T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon- (IFN-) signaling, and antigen presentation pathways provided protection of tumor cells from CD8+ T cell–mediated killing and blunted antitumor immune responses in vivo. Deletion of a number of genes in the TNF pathway also emerged as the key mechanism of immune evasion from primary NK cells. Our screens also identified that the metabolic protein 2-aminoethanethiol dioxygenase (Ado) modulates sensitivity to TNF-mediated killing by cytotoxic lymphocytes and is required for optimal control of tumors in vivo. Remarkably, we found that tumors delete the same genes when exposed to perforin-deficient CD8+ T cells, demonstrating that the dominant immune evasion strategy used by tumor cells is acquired resistance to T cell–derived cytokine-mediated antitumor effects. We demonstrate that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumor cells. In addition to highlighting the importance of TNF in CD8+ T cell– and NK cell–mediated killing of tumor cells, our study also provides a comprehensive picture of the roles of the TNF, IFN, and antigen presentation pathways in immune-mediated tumor surveillance.
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                Author and article information

                Journal
                Rheumatology (Oxford)
                Rheumatology (Oxford)
                brheum
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                December 2019
                09 December 2019
                09 December 2019
                : 58
                : Suppl 7 , The rheumatic side-effects of immuno-oncology treatment
                : vii29-vii39
                Affiliations
                [1 ] Institute of Immunology and Immunotherapy , Birmingham, UK
                [2 ] Institute of Inflammation and Ageing, University of Birmingham , Birmingham, UK
                [3 ] Cancer Centre, University Hospital Birmingham , Birmingham, UK
                [4 ] National Institute of Health Research Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospital Birmingham , Birmingham, UK
                Author notes
                Correspondence to: Neil Steven, University Hospital Birmingham, Heritage Building (Queen Elizabeth Hospital), Mindelsohn Way, Edgbaston, Birmingham B15 2TH, UK. E-mail: n.m.steven@ 123456bham.ac.uk
                Author information
                http://orcid.org/0000-0003-4631-549X
                Article
                kez536
                10.1093/rheumatology/kez536
                6900910
                31816079
                e3d090cc-ba1b-4fd7-bdd9-bdb59f3097ff
                © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 20 May 2019
                : 30 September 2019
                Page count
                Pages: 11
                Funding
                Funded by: NIHR Birmingham Biomedical Research Centre
                Funded by: National Health Service
                Funded by: National Institute for Health Research 10.13039/501100000272
                Funded by: Department of Health 10.13039/501100003921
                Funded by: BMS 10.13039/100002491
                Categories
                Supplement Articles

                Rheumatology
                immune checkpoint inhibitor,nivolumab,pembrolizumab,ipilimumab,melanoma,nsclc,arthritis,arthralgia,immune related adverse events,myositis

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