Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma.

Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, here we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PDL1) alone or in combination with tremelimumab (anti-CTLA4) from the CIAO clinical trial ( NCT03144778 ). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction in intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in participant tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PDL1 ICB, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of antitumor immunity and promotes immunotherapy resistance.