Commensal bacteria antigen-mediated immune response enhances anti-tumor immunity

Immunotherapy has transformed cancer treatments, but the majority of cancer patients would inevitably develop resistance to immunotherapy. Th17 cells play complex but crucial roles in anti-cancer immune response, although their therapeutic potential remains underutilized. Segmented filamentous bacteria (SFB) function as prototypical commensal bacteria that can induce intestinal Th17 cells and impact host immune response. In this study, we investigated how SFB antigen-mediated immune responses modify the tumor microenvironment and enhance anti-tumor efficacy through a coordinated gut-lung immunological axis. We engineered B16F1 melanoma cells to express either the SFB3340 epitope (B16-3340, an I-A^b-restricted epitope derived from SFBNYU_003340 and recognized by 7B8 TCR) or a control vector (B16-MEM) to evaluate SFB antigen effects on tumor immunogenicity. We found that expression of the SFB epitope in cancer cells decreased the number of lung tumor nodules, and SFB colonization further reduced tumor growth in a lung metastasis model. In addition, Th1, Th17, and CD8⁺ Tc1 cells were all increased in the lungs of the B16-3340 tumor-bearing mice compared with B16-MEM control tumor-bearing mice without triggering a compensatory expansion of immunosuppressive Tregs. Interestingly, SFB triggers systemic metabolic changes and an increase metabolites from aromatic amino acid degradation pathways, providing biochemical evidence for a functional gut-lung conduit, which integrates innate microbial detection with adaptive tumor-specific immunity. Our research provides evidence to further investigate and develop novel cancer immunotherapies that utilize microbial antigens and microbiome modifications to improve patient outcomes.