Abstract
BackgroundImmune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody is the first ICPI which has shown remarkable benefits in the clinical treatment of cancers. However, the increased activity of the immune system also causes some side effects called immune-related adverse events (irAEs). Colitis is one of the most common irAEs related to anti-CTLA-4 immunotherapy.ResultsWe identified that CD4+ T cells were the primary responders in CTLA-4 blockade and that the expansion of gut-homing CD4+ T cells by anti-CTLA-4 therapy was independent of CD103. We used dextran sulfate sodium (DSS)-induced colitis mice as our model and tested the possibility of using a trafficking-blocking antibody to treat anti-CTLA-4 antibody-induced irAEs. We found that blocking T cell homing increased colitis severity in the context of CTLA-4 blockade and that gut-trafficking blockade had different effects on different Th subsets and could facilitate the proliferation of Th17 cells in the lamina propria (LP).ConclusionsOur data reveals the fundamental mechanism underlying trafficking-blocking antibody therapy for CTLA-4 blockade-induced colitis and provide a caution in regard to apply trafficking-blocking antibody treatment under CTLA-4 blockade condition.
Highlights
Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies
The process of T cell homing to the gut requires β7-containing integrins. β7 is one of the integrin subunits; it noncovalently associates with the α4 subunit to become α4β7 integrin, which functions as a transmembrane cell adhesion receptor and is expressed on the surface of T cells. α4β7 integrin binds to its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is constitutively expressed on high endothelial venules, to mediate T cell extravasation from the blood to the gut mucosal tissues of the gut-associated lymphoid tissue (GALT), such as Peyer’s patches (PPs), mesenteric lymph node (MLN) and lamina propria (LP) [19, 20]
In the CD4+ subset, the percentage of activated gut-homing CD4+ T cells was increased over 2 times after antiCTLA-4 antibody treatment compared with control treatment, while there was no significant change in blood CD8+ T cells (Fig. 1a)
Summary
Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody is the first ICPI which has shown remarkable benefits in the clinical treatment of cancers. We used dextran sulfate sodium (DSS)-induced colitis mice as our model and tested the possibility of using a trafficking-blocking antibody to treat anti-CTLA-4 antibody-induced irAEs. We found that blocking T cell homing increased colitis severity in the context of CTLA-4 blockade and that gut-trafficking blockade had different effects on different Th subsets and could facilitate the proliferation of Th17 cells in the lamina propria (LP). Vedolizumab acts on gut-trophic α4β7 integrin and has been approved to treat inflammatory bowel disease (IBD) [22, 23]; etrolizumab, which is in the clinical trials for ulcerative colitis, can target and bind to the β7 subunit [24]. Clinical case series suggest that vedolizumab is effective for treating steroidrefractory enterocolitis caused by ICPIs [25]
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