Background Melanoma outlook has improved due to advances in immunotherapy, specifically anti-PD1 treatment. However, only about 50% of melanoma patients respond, and the barriers to their response remain unclear. Recent studies have shown that the composition of the gut microbiome is correlated with response to immunotherapy in melanoma patients, leading to the identification of a variety of bacterial strains of interest. However, the uniting characteristics of an immunotherapy responsive microbiome remain unknown. Previous work from our group shows that colonic colonization with Helicobacter hepaticus (Hhep) drives CD4+ T cell dependent anti-tumor immunity in a colorectal cancer model, but whether Hhep supports anti-tumor immunity at distant tumor sites is unknown. We hypothesize that cytotoxic Hhep-specific CD4+ T cells formed in response to Hhep colonization translocate to distant tumors to drive anti-tumor immunity in melanoma.
Methods Using the B16 mouse model of melanoma, an anti-PD1 resistant tumor, we combined Hhep colonization with anti-PD1 therapy to determine whether microbiome modulation could increase anti-PD1 efficacy. We monitored tumor growth and survival, endogenous T cell function, and overall T cell infiltration through flow cytometry and immunofluorescence. In addition, we assessed the fate and function of both Hhep-specific and tumor-specific T cells through transfer of TCR transgenic T cells.
Results We have shown that, when paired with anti-PD1 therapy, Hhep colonization drives anti-tumor immunity beyond the gut in an ICI-resistant melanoma tumor model. Hhep colonization paired with anti-PD1 increased overall infiltration of both CD8+ T cell and Hhep-specific CD4+ T cells. In addition, dual treatment was associated with a decreased percentage of intratumoral exhausted (PD1hi and PD1hiTim3+) endogenous CD4+ T cells.
Conclusions Here, we have found that the addition of a single bacterial species to the gut microbiome confers response to immunotherapy in a traditionally refractory melanoma mouse model. Our work builds on previous studies connecting bacterial species of interest with responsiveness to immunotherapy and furthers this understanding by identifying Hhep-specific CD4+ T cells in the tumor microenvironment as a potential mechanism by which the gut microbiome impacts distant anti-tumor immunity. Overall, these studies suggest that targeting the gut microbiota and microbiota-specific immune response may represent a new therapeutic target in immunotherapy-resistant tumors.
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