Peptostreptococcus anaerobius mediates anti-PD1 therapy resistance and exacerbates colorectal cancer via myeloid-derived suppressor cells in mice

Abstract Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α 2 β 1 –NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2 + MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC₂2, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α 2 β 1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius -mediated resistance to anti-PD1 therapy in CRC.