Lung cancer is an aggressive cancer that claims 160000 lives in the US annually. Our long-term goal is to develop treatment strategies that improve cure rates. To this end, we have been investigating immune therapy. Lung cancers recruit and activate diverse inflammatory cells, creating an immunosuppressive environment favoring growth and spread. We have developed genetic mouse models with the mutations found in human lung cancer for detailed study of tumor growth and response to immune therapies. As in many patients, targeting a molecule on cancer cells in these models that regulates killer T cell activity, called programmed death ligand 1 (PD-L1), can provide partial benefit. Unfortunately...

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Lung cancer is an aggressive cancer that claims 160000 lives in the US annually. Our long-term goal is to develop treatment strategies that improve cure rates. To this end, we have been investigating immune therapy. Lung cancers recruit and activate diverse inflammatory cells, creating an immunosuppressive environment favoring growth and spread. We have developed genetic mouse models with the mutations found in human lung cancer for detailed study of tumor growth and response to immune therapies. As in many patients, targeting a molecule on cancer cells in these models that regulates killer T cell activity, called programmed death ligand 1 (PD-L1), can provide partial benefit. Unfortunately the treatment is not durable due to an insufficient immune response. One factor that drives resistance to PD-L1 blockade is the expression of CD38. CD38 acts outside of cells to break down several metabolites and produce high local adenosine concentrations, which can suppress T cell activity. We found that immunotherapy combinations work better with CD38 inhibitors, by increasing T cell activation and sustaining anti-tumor immunity. Findings in the mouse models were confirmed by examination of several large lung cancer datasets. We believe that targeting CD38 together with immune modulators like PD-L1 will more effectively harness the immune system to attack tumor cells. To build clinically effective strategies we need to identify patients most likely to benefit and frame a detailed view of how tumors respond to anti-PD-L1/-CD38 treatment. Building on our findings toward immediate translational impact, this proposal uses unique mouse models and human lung tumor samples to 1) study the mechanism(s) by which CD38 produces immunosuppression within tumors, 2) define the interactions of other immune cell types besides T cells during this process, and 3) investigate the relationship of CD38 to the tumor and immune system characteristics in deeply annotated patient tumor sets.

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