Investigating microbiome-based anti-tumor immune modulation using patient-derived mouse models

Abstract

Abstract Growing data supports that the gut microbiota can impact cancer immunotherapy. We previously found certain bacterial taxa associated with response to immune checkpoint blockade. These correlations warrant deeper mechanistic studies using tractable mouse models to establish the role of the microbiota in determining immunotherapy efficacy. To understand how the microbiota affects anti-tumor immunity we generated patient-based microbiota models. Germ-free mice were colonized using patient feces, bred, and subsequent generations studied using transplantable tumor models. We focused on two representative patient-based models: one from a responder (R) to immunotherapy and one from a non-responder (NR). Mice established from the R demonstrated greater benefit from anti-PD-L1 therapy compared to NR colonized mice and had superior CD8+ T cell responses with greater accumulation of tumor-specific CD8+ T cells and increased proliferation. In addition, compared to NR-derived mice, R-derived mice had increased intra-tumoral CD103+ dendritic cells (DCs), as well as increased BATF3-lineage DCs in the mesenteric lymph nodes and spleen. In agreement with a stronger anti-tumor immune response, R mice had higher circulating levels of IFN-γ, IL-12p70, and CXCL5 compared to NR mice. To identify potential systemic signals originating from the gut microbiome and capable of altering global immune populations we profiled serum using an unbiased metabolomics-based approach. We found distinct metabolite profiles in the R- and NR-derived mice, suggesting potential bacteria-derived or -modified metabolite modulating immune function. These data support a role for the gut microbiome determining host sensitivity to cancer immunotherapy.