Sensitizing tumor cells to immunotherapy by postbiotic-mediated upregulation of HLA class I

Recent data have shown that gut microbiota have a major impact on the clinical response to immune checkpoint inhibitors (ICIs). ICI therapy acts by unlocking tumor antigen (TA)-specific T cells and cancer clearance by TA-specific T cells requires expression of relevant TAs on cancer cells’ HLA class I molecules. Reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system, prompting out hypothesis that the presence of certain bacteria can enhance patients’ immune responses by upregulating HLA class I expression on cancer cells. Here we show that metabolites released by bacteria, known as postbiotics, can upregulate HLA class I expression on cancer cells of melanoma, breast, and leukemic origin in vitro, which sensitizes them to TA-specific T cell lysis. This effect was recapitulated in vivo, as postbiotic administration resulted in upregulated MHC class I expression on cancer cells and increased number of tumor-specific CD8+ T cells. When combined with anti-PD-1 ICI and adoptive cell therapy, postbiotics controlled tumor growth when compared to combination treatment with the vehicle control. Our results thus far indicate that one mechanism of action of the microbiota in favoring ICI efficacy is via the increase in HLA class I expression on the surface of cancer cells, which leads to increased recognition by TA-specific T cells both in vitro and in vivo. These results suggest that postbiotics could be explored in combination with ICIs to enhance clinical anti-cancer immune responses.