Immune Checkpoint Inhibitor Colitis: Resident Memory Unleashed
2021; Elsevier BV; Volume: 161; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2021.07.007
ISSN1528-0012
Autores Tópico(s)Colorectal Cancer Treatments and Studies
ResumoSee “Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis,” by Sasson SC, Slevin SM, Cheung VT, et al, on page 1229. See “Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis,” by Sasson SC, Slevin SM, Cheung VT, et al, on page 1229. The immune system orchestrates a delicate balance between inflammation and tolerance. Over the past 2 decades, we have learned that this balance generally favors tumor growth, and that manipulation of tolerance can induce potent antitumor immunity.1Schumacher T.N. Schreiber R.D. Neoantigens in cancer immunotherapy.Science. 2015; 348: 69-74Crossref PubMed Scopus (2675) Google Scholar Monoclonal antibodies that inhibit the immune regulatory checkpoint receptors cytotoxic T-lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and its ligand (PD)-L1 lead to robust clinical responses in a subset of previously untreatable cancers and can even induce durable remissions.2Ribas A. Wolchok J.D. Cancer immunotherapy using checkpoint blockade.Science. 2018; 359: 1350-1355Crossref PubMed Scopus (2387) Google Scholar The success of immune checkpoint inhibitors (ICIs) has been somewhat limited by a range of inflammatory toxicities induced by blocking these key tolerance mechanisms.3Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Crossref PubMed Scopus (1737) Google Scholar Gastrointestinal (GI) toxicities are among the most common severe complications of ICIs, with colitis being the most prevalent GI toxicity.4Wang D.Y. Salem J.E. Cohen J.V. et al.Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.JAMA Oncol. 2018; 4: 1721-1728Crossref PubMed Scopus (859) Google Scholar Nearly all guidelines are based on analogy to treatment of inflammatory bowel disease (IBD), retrospective analyses, and small case series.5Dougan M. Wang Y. Rubio-Tapia A. et al.AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review.Gastroenterology. 2021; 160: 1384-1393Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The clinical problem is made more complex because any intervention to treat colitis may risk inhibiting potentially life-saving antitumor responses.6Pauken K.E. Dougan M. Rose N.R. et al.Adverse events following cancer immunotherapy: obstacles and opportunities.Trends Immunol. 2019; 40: 511-523Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Understanding the mechanisms driving ICI colitis, and the inflammatory toxicities of ICIs more generally, is a critical first step in developing strategies that treat colitis and preserve antitumor responses. Until recently, the mechanisms driving ICI toxicities were poorly understood because no detailed immune analyses had been performed on inflamed tissue. We now know that ICI colitis is characterized by an expansion of IFN-γ positive, granzyme B+ cytotoxic CD8+ T cells, and to a lesser extent TH1 skewed CD4+ T cells, expanded T regulatory cells, and inflammatory macrophages.7Luoma A.M. Suo S. Williams H.L. et al.Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.Cell. 2020; 182: 655-671 e22Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In this issue of Gastroenterology, Sasson et al8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar add to the body of evidence that these CD8+ T cells unleased by ICIs originate from the tissue resident memory (Trm) pool of the GI mucosa.8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The authors find a large pool of activated CD8+ T cells that express CD103, characteristic of Trm cells, in the colons of patients with ICI colitis (Figure 1).8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar These expanded Trms were not present in immunotherapy-treated patients without colitis or in healthy controls. These findings complement a previous analysis of shared T-cell receptor sequences that had demonstrated that many of the CD8+ T-cell clones expanded in ICI colitis were shared with the Trm pool.7Luoma A.M. Suo S. Williams H.L. et al.Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.Cell. 2020; 182: 655-671 e22Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The current report expands on previous knowledge in several ways. Sasson et al8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar clearly demonstrate that expanded Trm cells are found not only in patients with ICI colitis, but also in the inflamed stomachs of patients with ICI gastritis, suggesting a shared mechanism across these toxicities. This finding further increases the likelihood that toxicities in other barrier organs such as the lungs and skin may arise from a similar expansion of Trms.9Dougan M. Luoma A.M. Dougan S.K. et al.Understanding and treating the inflammatory adverse events of cancer immunotherapy.Cell. 2021; 184: 1575-1588Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar What remains unclear is why individual patients develop inflammation in some luminal organs and not others, and whether this is driven by differences in the Trm pool at different sites.10Badran Y. Shih A. Leet D. et al.Immune checkpoint inhibitor-associated celiac disease.J Immunother Cancer. 2020; 8Crossref PubMed Scopus (17) Google Scholar Furthermore, integrin inhibitors that block trafficking of effector T cells into the GI tract are effective for ICI colitis treatment.11Abu-Sbeih H. Ali F.S. Alsaadi D. et al.Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.J Immunother Cancer. 2018; 6: 142Crossref PubMed Scopus (87) Google Scholar Thus, even though ICI colitis is largely dominated by Trms, effector T cells recruited from the circulation likely play a role in perpetuating ICI colitis. This finding is consistent with the observed high expression of gut homing integrins and inflammatory chemokines and their receptors in ICI colitis, and with the presence of expanded clones with TCRs that do not match the Trm population, particularly among CD4+ T cells.7Luoma A.M. Suo S. Williams H.L. et al.Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.Cell. 2020; 182: 655-671 e22Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,11Abu-Sbeih H. Ali F.S. Alsaadi D. et al.Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.J Immunother Cancer. 2018; 6: 142Crossref PubMed Scopus (87) Google Scholar The authors also compare colitis from combination CTLA-4 and PD-1 inhibitors with colitis from PD-1 inhibitors alone. This analysis is the first to make this comparison with this level of immunologic detail. They find that both forms of colitis demonstrate an expanded Trm population, consistent with a shared mechanism, although the limited number of cells sampled may have masked subtle differences between these 2 forms of colitis, which differ in their clinical presentations.8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The authors’ analysis further compares ICI colitis to ulcerative colitis, the type of IBD that it most resembles, finding no such expansion of CD8+ Trms and a relative induction of CD4+ T cells.8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar One of the limitations of this analysis was that, although patients with ulcerative colitis were analyzed during a flare, each had harbored disease for much longer than the patients with ICI colitis.8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The differences noted may, therefore, be related to chronicity rather than to fundamental differences in mechanism. Patients with IBD are at much higher risk for developing checkpoint colitis, suggesting a mechanistic connection between the 2 diseases.12Abu-Sbeih H. Faleck D.M. Ricciuti B. et al.Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease.J Clin Oncol. 2020; 38: 576-583Crossref PubMed Scopus (74) Google Scholar Sasson et al8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar find levels of IFN-γ consistently elevated in ICI colitis, corroborating earlier findings and emphasizing the importance of this cytokine in driving ICI colitis.9Dougan M. Luoma A.M. Dougan S.K. et al.Understanding and treating the inflammatory adverse events of cancer immunotherapy.Cell. 2021; 184: 1575-1588Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar As was done empirically in a previously reported case series, the authors then use a JAK inhibitor to successfully treat a patient with refractory ICI colitis based on these data.8Sasson S.C. Slevin S.M. Cheung V.T. et al.Interferon-gamma–producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis.Gastroenterology. 2021; 161: 1229-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,13Bishu S. Melia J. Sharfman W. et al.Efficacy and outcome of tofacitinib in immune checkpoint inhibitor colitis.Gastroenterology. 2020; 160: 932-934Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar IFN-γ also has a well-established role in mediating effective antitumor responses to ICIs. In animal models, mutations in IFN-γ signaling are among the most common mechanisms of resistance to ICIs.14Manguso R.T. Pope H.W. Zimmer M.D. et al.In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.Nature. 2017; 547: 413-418Crossref PubMed Scopus (481) Google Scholar In patients, IFN-γ–producing T cells are highly correlated with effective antitumor responses, and mutations in IFN-γ signaling are associated with acquired resistance to treatment.15Sade-Feldman M. Yizhak K. Bjorgaard S.L. et al.Defining T cell states associated with response to checkpoint immunotherapy in melanoma.Cell. 2018; 175: 998-1013 e20Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar,16Zaretsky J.M. Garcia-Diaz A. Shin D.S. et al.Mutations associated with acquired resistance to PD-1 blockade in melanoma.N Engl J Med. 2016; 375: 819-829Crossref PubMed Scopus (1718) Google Scholar The effective management of ICI colitis must consider the consequences of therapy on the cancer. Consequently, although JAK inhibitors are a reasonable last line therapy for patients with refractory ICI colitis, alternative strategies such as integrin inhibitors or tumor necrosis factor-α blockade should be considered first.5Dougan M. Wang Y. Rubio-Tapia A. et al.AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review.Gastroenterology. 2021; 160: 1384-1393Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,17Bertrand F. Montfort A. Marcheteau E. et al.TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma.Nat Commun. 2017; 8: 2256Crossref PubMed Scopus (174) Google Scholar This report is another step in understanding the immune mechanisms driving ICI colitis, confirming a key role for CTLA-4, PD-1, and PD-L1 in regulating Trms throughout the gut, and indicating key distinctions between ICI colitis and IBD. Next steps should focus on determining whether the Trm population differs at baseline between those who develop ICI colitis and those who do not, as well as establishing a clearer picture of the differences between CTLA-4 and PD-1/PD-L1 inhibition. How therapies for ICI colitis influence Trms and whether these cells return to their baseline state will also be important to understand. Most critically, a more detailed assessment of the mechanistic differences between ICI colitis and effective antitumor immunity will be necessary to develop more tailored next line therapies. Interferon-Gamma–Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor–ColitisGastroenterologyVol. 161Issue 4PreviewWe present an analysis of the immunopathology in checkpoint-inhibitor colitis, a common adverse effect of cancer immunotherapy. We used our findings to successfully identify a novel therapy for a case of refractory colitis. Full-Text PDF Open Access
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