Lack of TREM2 during anti-PD1 therapy reprograms intestinal macrophages and microbiota to enhance tumor rejection

The gut microbiota and tumor-associated macrophages (TAM) impact anti-PD1 checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor TREM2 attenuates tumor growth; lack of functional TREM2 enhances tumor elimination by anti-PD1. We found that anti-PD1 combined with TREM2 deficiency induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus (R. gnavus) in the gut microbiota. Colonization of wild-type mice with R. gnavus recapitulated enhancement of anti-PD1-mediated tumor elimination occurring in the absence of TREM2. The intestinal proinflammatory environment coincided with expansion, increased circulation and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD1 checkpoint blockade through modulation of the intestinal immune environment and microbiota; R. gnavus is a potential probiotic agent for overcoming resistance to anti-PD1.