Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities

Coutzac, Clélia; Adam, Julien; Soularue, Émilie; Collins, Michael; Racine, Antoine; Mussini, Charlotte; Boselli, Lisa; Kamsu‐Kom, Nyam; Mateus, Christine; Charrier, Mélinda; Cassard, Lydie; Planchard, David; Ribrag, Vincent; Fizazi, Karim; Loriot, Yohann; Lepage, Patricia; Scoazec, Jean‐Yves; Robert, Caroline; Carbonnel, Franck; Chaput, Nathalie

doi:10.1093/ecco-jcc/jjx081

Cited by 122 publications

(119 citation statements)

References 38 publications

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“…This is most likely an immune‐mediated toxicity effect related to the antibody treatment. This is also evident in anti‐PD1‐induced colitis biopsies from humans, where CD8+ T‐cells were predominant in the intestinal epithelium and lamina propria . Thus, a clinical concern could be the potential risk of adverse events in patients with a preexisting autoimmune disorder, such as IBD patients receiving checkpoint‐blocking antibodies.…”

Section: Discussionmentioning

confidence: 92%

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

et al. 2019

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Summary Chronic inflammation may drive development of cancer as observed in inflammation‐induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti‐tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein‐1 (PD‐1)/PD‐L1 signalling pathway is currently at the forefront in the development of anti‐tumour immunity‐based therapies for multiple malignancies. By blocking the immune‐checkpoint of activated T‐cells, it is possible to rewire the adaptive resistance induced by the PD‐1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy‐modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T‐cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)‐induced colitis and colitis‐associated CRC. In addition, we examined the expression of PD‐1 and its ligands PD‐L1 and PD‐L2 as well as other molecular targets related to T‐cell exhaustion. We found a significant increase in PD‐1 expression on all examined mucosal T‐cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD‐L1 and PD‐L2 mRNA expression throughout the AOM/DSS regime. Blocking PD‐1 signalling with an anti‐PD1 antibody did not affect the tumour burden in the AOM/DSS‐treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune‐mediated toxicity. This raises a concern for patients with colitis‐associated CRCs and should be further investigated.

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Section: Discussionmentioning

confidence: 92%

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

et al. 2019

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“…In patients who experienced recurrent anti-PD-1 colitis, features of chronicity such as basal lymphoplasmacytosis and crypt architectural irregularity are reported many months after cessation of anti-PD-1 therapy 62. Colonic mucosal lymphocytes are predominantly CD8+ T cells in anti-PD-1-induced colitis,45 which differs from the predominance of CD4+ T cells observed in anti-CTLA-4-induced colitis 68 69…”

Section: Resultsmentioning

confidence: 99%

“…Microscopic colitis has also been diagnosed in patients treated with anti-CTLA-4 antibodies 25 44 45. Interestingly, predominance of mucosal CD4+ lymphocytes in anti-CTLA-4-induced colitis was observed, with significantly higher tumour necrosis factor (TNF)-α secretion in anti-CTLA-4-induced colitis than in anti-PD-1-induced colitis 45. Histological inflammation of the stomach and the duodenum have been reported in 55% of patients treated with ipilimumab 25.…”

Section: Resultsmentioning

confidence: 99%

Enterocolitis due to immune checkpoint inhibitors: a systematic review

Soularue

Lepage

Colombel

et al. 2018

Gut

Self Cite

196

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Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.

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“…These immunosuppressive Tregs constitutively express high levels of CTLA‐4, and increased incidence of autoimmune disease was found in mice lacking Tregs . The lamina propria and epithelium of the colon in anti‐PD‐1‐induced colitis have been predominantly characterized by CD8+ T cells and Tregs, whereas the lamina propria of the colon in anti‐CTLA‐4‐induced colitis has been predominantly characterized by CD4+ T cells and high mucosal TNF‐α concentrations . Colitis related to anti‐CTLA‐4 treatment has features similar to graft‐versus‐host disease .…”

Section: Mechanism Of Immune Therapy–induced Colitismentioning

confidence: 99%

Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors

Singh

Marshall

2019

The Oncologist

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As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side‐effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune‐mediated toxicities need special attention. One of the most common is immune‐mediated colitis. Workup and management of immune‐mediated colitis can be challenging and is the purpose of this review. Key Points Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune‐mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.

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Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities

Abstract: These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFα concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.

Cited by 122 publications

References 38 publications

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

Enterocolitis due to immune checkpoint inhibitors: a systematic review

Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors

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