MICROBIAL-DERIVED IMMUNOSTIMULATORY SMALL MOLECULE SYNERGIZES WITH ANTI-PD-1 THERAPY IN LUNG CANCER

We previously showed that enrichment of the Bacteroides genus is associated with improved anti-PD-1-mediated tumor therapy in a mouse model of non-small cell lung cancer (NSCLC). Here we isolated and identified 183 Bacteroides isolates from humanized anti-PD-1 responder mice feces. Supernatants from 6 out of 183 isolates stimulated IFNgamma production from primary CD8+ T cells. These 6 isolates (6-consort) enhanced anti-PD-1-induced anti-tumor efficacy compared to non-responder feces-colonized mice, an effect dependent on production of IFNgamma. Bioassay guided fractionation coupled with comparative metabolomics analysis led to the discovery of an active N-acyl amide (cis-Bac429) produced by Bacteroides. Cis-Bac429 robustly stimulates IFNgamma in a dose-dependent manner in CD8+ T cells, while synthetic saturated Bac429 (sat-Bac429) does not, indicating structural specificity. Intratumorally administered cis-Bac429 but not sat-Bac429 significantly decreases tumor growth in combination with anti-PD-1 therapy and drives CD8+ T cell tumor infiltration. These findings pave the way for development of Bacteroides-type N-acyl-amides as adjuvant treatments for anti-PD-1-refractory NSCLC.