Immunotherapy efficacy is dependent on an immune cell-microbiota circuit in colorectal cancer

Cancer is the second most common cause of death globally. Checkpoint blockade therapies enhance the anti-tumor capabilities of the immune system have revolutionized the treatment of various cancer. The efficacy of these therapies was recently shown to depend on specific bacteria. Most colorectal cancers are resistant to this treatment and we therefore aimed at identifying specific bacteria with efficacy in colorectal cancer. Moreover, the nature through which bacteria enhance checkpoint blockade therapies is unknown. Here, we identified three specific bacteria enhancing the efficacy of checkpoint blockade therapies in cancer. Mechanistically, on a cellular level a breakdown of the gut barrier allowed for translocation of bacterial products and cancer protective Th1 differentiation. Conditional depletion revealed a dependency on classical dendritic cells and IL-12 production for efficient anti-tumor immunity. On a molecular level, inosine, engaged A2A receptor - cyclic AMP - Proteine kinase A-phosphoCREB signaling in T-cells which induced Th1 differentiation. Lastly, we also show that bacteria-elicited checkpoint blockade therapy efficacy differs in distinct subtypes of colorectal cancer, revealing the strengths and limitations of bacterial co-therapy in cancer. This work will further drive bacteria-checkpoint blockade co-therapies and guide precision medicine approaches in colorectal cancer.