Crossreactivity between MHC class I-restricted antigens from cancer cells and an enterococcal bacteriophage

It has been speculated that the intestinal microbiota induces commensal-specific memory T cells that then cross-react with tumor-associated antigens. Here, we identified MHC class I-binding epitopes within the tail length tape measure protein (TMP) of a prophage found in the genome of Enterococcus hirae. Mice bearing E. hirae strains harboring this prophage mounted a TMP-specific H-2Kb restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD1 antibodies. Such TMP-specific T cells also recognized a 78% identical H-2K -binding peptide derived from the proteasome (20S) subunit beta type-4 (PSMB4), allowing them to control mouse tumors expressing this oncogenic driver. Administration of bacterial strains engineered to express the TMP epitope improved the outcome of immunotherapy. Tumors bearing PSMB4 knock-in mutations that abolish crossreactivity with TMP became immunotherapy-resistant. In renal and lung cancer patients, the presence of the enterococcal prophage in stools, as well as the expression of a TMP-cross reactive antigen by tumors, predicted the long-term benefit of PD-1 blockade. In melanoma patients, we detected T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides. Altogether, these results support the idea that intestinal microbe-specific T cell responses contribute to anticancer immunosurveillance.