TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti–PD-1 tumor immunotherapy
Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natália Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José Luís Fachi, Bishan Bhattarai, Tihana Tršan, Patrick Fernandes Rodrigues, Jinchao Hou, Jennifer K. Bando, Cristiane Sécca, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna
Abstract
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4 + T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.