Data from <i>Faecalibacterium prausnitzii</i> Abrogates Intestinal Toxicity and Promotes Tumor Immunity to Increase the Efficacy of Dual CTLA4 and PD-1 Checkpoint Blockade

Abstract

<div>Abstract<p>Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and <i>Faecalibacterium prausnitzii</i> (<i>F. prausnitzii</i>) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of <i>F. prausnitzii</i>. <i>In vivo</i>, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. <i>F. prausnitzii</i> administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, <i>F. prausnitzii</i> enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of <i>F. prausnitzii</i> increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. <i>F. prausnitzii</i> abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that <i>F. prausnitzii</i> administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy.</p>Significance:<p><i>F. prausnitzii</i> alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with <i>F. prausnitzii</i> could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.</p></div>