Mechanism of microbiota-mediated potentiation of checkpoint blockade efficacy in lung cancer

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The discovery that the host immune system can be harnessed to attack solid tumors and improve overall survival for patients has been transformative. However, only certain tumors are responsive to immune checkpoint blockade, and an unpredictable fraction maintain durable remissions. In addition, similarly unpredictable toxicity can manifest with diverse autoimmune attack of normal tissue. Beyond PD-L1 staining and mutational burden, we have limited biomarkers of response, and we have no predictors of autoimmune toxicities. Recent studies have highlighted the contribution of the intestinal microbiota to successful PD-1/PD- L1 and CTLA-4 antibody blockade. There is, however, no consensus as to which microbes promote effective anti-tumor immune responses, and we lack an understanding of the mechanisms involved. In our proposed studies, we will seek to identify human gut-associated bacterial species and products that enhance control of lung adenocarcinoma growth following anti-PD-1 immunotherapy. We will then characterize the host cellular and molecular targets of the bacteria and their products. In preliminary studies, we identified a strain of Bacteroides vulgatus that promotes autoimmune disease and also restricts growth of implanted lung cancer cells in anti-PD-1-treated mice. This tumor model will be used to assess the immune-potentiating roles of B. vulgatus genes, such as those involved in synthesis of capsular polysaccharides and Lipid A, and to screen bacterial libraries prepared from patient super-responders, to identify species and consortia that are most effective at supporting inhibition of tumor growth. We have also developed an autochthonous lung cancer model in which neoantigens accumulate due to targeting of the mismatch repair machinery, and we will assess the ability of the candidate microbes to function in a therapeutic mode, after growth of the spontaneous tumors is established. We will then characterize differences in metabolites and proteins within lymph draining the intestine of mice colonized with immunotherapy-potentiating or control microbes, and candidate molecules will be evaluated for their activity in the tumor models. Lastly, we will seek to identify the innate signaling pathways and the relevant host target cells that convey microbial signals to the tumor microenvironment, thus enhancing immune control of tumor growth following anti-PD-1 administration. Since tumor cell killing is mediated by cytotoxic T cells, we will also determine if there are shared antigenic specificities between tumors and the microbiota. These studies will be complemented by spatial transcriptomic analyses of tumor microenvironments from mice with and without immunotherapy-potentiating microbiota. Serum from responder and non-responder lung cancer patients will be evaluated for the presence of microbiome-dependent products identified in the mouse model and tumor tissue specimens will be subjected to spatial transcriptomics analysis to determine if there are features shared with tumors in mice. Together, these studies can provide insights for designing rational strategies to utilize microbiota for potentiation of immune checkpoint blockade in cancer.