Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapyinduced colitis

Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients.

Automated summary

Immune-related adverse events pose a significant obstacle to the success of immunotherapy. This study investigates the immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy in patients with colitis. The researchers found distinct repertoire changes in patients with moderate-severe colitis, regardless of their antitumor response. The expansion of circulating monocytes and T cells was greater in patients with colitis, and specific T cell subsets were expanded in the inflamed regions of the colon. The data suggests that exaggerated innate and T cell responses contribute to colitis in susceptible patients.