Transcriptomic profile comparison of an in vivo model of dual combination immune checkpoint colitis or monotherapy immune checkpoint colitis

Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. A higher proportion of patients undergoing monotherapy anti-CTLA-4 treatment tend to develop colitis compared to monotherapy treated anti-PD-1 treated patients. This effect is enhanced when patients are treated with both drugs. To probe the impact of either anti-CTLA4 or anti-PD1 on intestinal homeostasis, mice were challenged with anti-CTLA-4 and anti-PD-1 immunotherapy in either monotherapy or together in combination. Manipulation of the intestinal microbiota has also been shown to be important in both this model, from previous data, and in patients. Colonic immune responses were then profiled using bulk RNA-sequencing. Comparative analysis of transcriptomic profiles from distal colon segments of untreated Balb/c wild type mice compared to Balb/c wild type mice treated with either anti-CTLA-4 monotherapy, anti-PD-1 monotherapy, or mice treated with both of these. All mice treated with immune checkpoint druh were given an oral gavage of a proinflammatory microbiota at the beginning. All treatments lasted 3 weeks.