Inflammation is a critical immune response that acts to recruit inflammatory cells to sites of infection and initiate protective immune responses; however, chronic inflammation promotes oncogenesis and tumor growth. While the pathogen-associated triggers of inflammation are well characterized, the molecular mechanisms that trigger chronic inflammation in cancer remain unclear. To clarify mechanisms that induce cancer-associated inflammation, I will investigate how activation of the NLRP1 inflammasome contributes to inflammation in cancer. 

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Inflammation is a critical immune response that acts to recruit inflammatory cells to sites of infection and initiate protective immune responses; however, chronic inflammation promotes oncogenesis and tumor growth. While the pathogen-associated triggers of inflammation are well characterized, the molecular mechanisms that trigger chronic inflammation in cancer remain unclear. To clarify mechanisms that induce cancer-associated inflammation, I will investigate how activation of the NLRP1 inflammasome contributes to inflammation in cancer.

NLRP1 is a cytosolic immune sensor activated by the enzymatic activities of pathogen-secreted proteins. Pathogen-secreted enzymes that target NLRP1 for proteasomal degradation activate the NLRP1 inflammasome, resulting in the release of inflammatory cytokines. At the same time, NLRP1 is highly relevant for several cancers. Mutations in NLRP1 are associated with autoinflammatory disease and increase risk for squamous cell carcinomas; NLRP1 induces inflammation in response to UV radiation, a key risk for melanoma; and NLRP1 expression is an unfavorable prognostic marker in renal cell cancers. The molecular mechanisms that activate NLRP1 in these cancers remain unclear.

The goal of Aim 1 of this proposal is to determine the mechanisms and pathways that activate NLRP1 in cancer. While chronic inflammasome activation promotes tumorigenesis, recent work shows that intentional activation of inflammasomes within tumors can recruit immune cells and promote tumor clearance. However, pharmacological activators and inhibitors of inflammasomes are lacking. In Aim 2, I will develop inhibitors and activators of the NLRP1 inflammasome. These tools will allow detailed characterization of the roles of the NLRP1 inflammasome in vivo, while also serving as potential starting points for the development of therapeutic agents to treat NLRP1-associated inflammation.

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