Lack of TREM2 during anti-PD-1 therapy reprograms intestinal macrophages and microbiota to enhance tumor rejection

The gut microbiota and tumor-associated macrophages (TAM) impact anti-PD-1 checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor TREM2 attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 combined with TREM2 deficiency induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus (R. gnavus) in the gut microbiota. Gavage of wild-type mice with R. gnavus recapitulated enhancement of anti-PD-1-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-PD-1 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. We performed single-cell RNA sequencing on intestinal myeloid cells , as well as bulk RNA-seq on total colonic tissue, from WT and TREM2-deficient mice treated or not with anti-PD-1. We also performed single-cell RNA sequencing on tumor immune cells from WT mice treated or not with Ruminococcus gnavus. Details for HTO Antibodies: HTO: Barcode Sequence: Hashtagged sample TotalSeq™-B0301 anti-mouse Hashtag 1 Antibody: ACCCACCAGTAAGAC: First biological sample harvasted from WT mice either treated or not with Ruminococcus gnavus gavage. TotalSeq™-B0302 anti-mouse Hashtag 2 Antibody: GGTCGAGAGCATTCA: Second biological sample harvasted from WT mice either treated or not with Ruminococcus gnavus gavage. TotalSeq™-B0303 anti-mouse Hashtag 3 Antibody: CTTGCCGCATGTCAT: Third biological sample harvasted from WT mice either treated or not with Ruminococcus gnavus gavage. TotalSeq™-B0303 anti-mouse Hashtag 4 Antibody: AAAGCATTCTTCACG: Forth biological sample harvasted from WT mice either treated or not with Ruminococcus gnavus gavage.