Investigating the role of Candida albicans gastrointestinal colonization on immune checkpoint therapy 2305444

Abstract Introduction Immune checkpoint therapies (ICTs) have revolutionized cancer treatment, yet most patients remain unresponsive. While the gut bacterial microbiota can influence ICT efficacy, the contribution of the gut fungal mycobiota remains poorly understood. Candida albicans (Ca), a predominant commensal fungus in the human gut, is linked to worse outcomes in several cancers. Additionally, a recent clinical study reported higher levels of Ca colonization in melanoma patients with poor responses to anti—PD-1 therapy. Using preclinical tumor models, we aim to investigate how gastrointestinal colonization with Ca affects ICT immune response. Methods C57BL/6 mice were orally colonized with Ca every other day, starting one week before tumor inoculation until the end of the experiment. When tumors reached ∼80 mm³, mice received ICT (anti—PD-1 +/- anti—CTLA-4) intraperitoneally every four days, for three doses. Mesenteric lymph nodes and tumor-draining lymph nodes were immunophenotyped before ICT initiation or 24 hours after the second dose. Results Ca colonization significantly impaired immune checkpoint therapy (ICT) efficacy in B16-F10 melanoma—bearing mice but not in MC38 colorectal tumor—bearing mice. This inhibitory effect in melanoma was dependent on an intact gut bacterial microbiota, as antibiotic treatment abrogated the phenotype. Immunophenotyping revealed a marked accumulation of RORγt+CD4+ (Th17) cells in mesenteric and tumor-draining lymph nodes of colonized mice both before and after ICT administration. In addition, Ca colonization was associated with an increase in neutrophils in tumor draining lymph nodes prior to ICT, possibly contributing to the development of an immunosuppressive microenvironment. Conclusion These findings suggest that Ca colonization compromises ICT efficacy in a microbiota-dependent manner, potentially through Th17-driven immunosuppressive mechanisms. Ongoing work will define how Ca alters gut bacterial composition and metabolites to modulate anti-tumor immunity. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)