Translocation of Gut Bacteria Enhances the Response to Immunotherapy

Gut microbiota, especially gut bacteria, have been associated with clinical response to immune checkpoint inhibitor therapy (ICT), but how these gut bacteria modulate the immune response to tumors outside the intestine and which species are involved remain unclear. To determine the effects of gut microbiota on extraintestinal antitumor immune responses and immunotherapy response, Choi and colleagues used an immunocompetent mouse model of melanoma and showed that, upon combination anti–CTLA-4 and anti–PD-1 treatment, tumor-bearing mice had bacterial translocation into tumors and secondary lymphoid organs, most notably the mesenteric lymph nodes (MLN). The dominant taxa identified in these tissues were Enterococcus faecalis during early phases of ICT treatment and Lactobacillus johnsonii after the second ICT dose, with neither species being highly abundant in the gut prior to treatment, suggesting ICT induced their specific translocation. Both species of bacteria, but not the common commensal gut bacteria Lactobacillus acidophilus, significantly activated mouse dendritic cells (DC) ex vivo, leading to high levels of CD8⁺ T-cell priming and activation. Removal of the MLN, but not the tumor-draining lymph node or spleen, reduced extraintestinal bacterial load, leukocyte infiltration of tumors, as well as DC and T-cell activation, which subsequently led to increased tumor growth and reduced survival in mice treated with ICT. Moreover, depletion of DCs or the chemokine receptor CCR7 abolished bacterial translocation into the MLN, and DCs isolated from the MLN of ICT-treated mice not only were more numerous but also carried higher bacterial loads compared to untreated mice. Furthermore, ICT was found to increase lymphangiogenesis and dilation of high endothelial venules in the MLN, which led to increased bacterial translocation. Finally, mice treated with antibiotics prior to tumor implantation exhibited reduced DC and CD8⁺ T-cell activation in response to ICT. In summary, this study shows that the translocation of gut bacteria can alter the effects of ICT, providing insight into why different taxa of the gut microbiome may be critical for ICT efficacy, and suggests that therapeutically targeting this phenotype could improve outcomes after treatment with ICT.

Choi Y, Lichterman JN, Coughlin LA, Poulides N, Li W, Del Valle P, et al. Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Sci Immunol 2023;8:eabo2003.

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