Cancerous tumors contain a complex mixture of different cell types including not only the culprit cancer cells but also normal tissue and immune cells. Called stromal cells, these are otherwise normal cells called in to perform abnormal functions, providing nutritional and structural support and immunologic protection of the resident cancer cells. Without the help of these supporting cells, tumors cannot progress. Few treatment regimens target these genetically normal cells, which, unlike cancer cells, cannot rely on mutations to escape targeted treatment regimens. Endothelial cells, which form new blood vessels that serve tumors, are an example of stromal cells that take on abnormal fun...

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Cancerous tumors contain a complex mixture of different cell types including not only the culprit cancer cells but also normal tissue and immune cells. Called stromal cells, these are otherwise normal cells called in to perform abnormal functions, providing nutritional and structural support and immunologic protection of the resident cancer cells. Without the help of these supporting cells, tumors cannot progress. Few treatment regimens target these genetically normal cells, which, unlike cancer cells, cannot rely on mutations to escape targeted treatment regimens. Endothelial cells, which form new blood vessels that serve tumors, are an example of stromal cells that take on abnormal functions to serve cancer cells. Tumor endothelial cells form aberrant blood vessels that create a tumor niche and are also instructed by cancer cells to downregulate anticancer immunity. For this proposal, we discovered that tumor endothelium selectively activates a process known as autophagy, which is required to serve tumors but is dispensable for the endothelium of normal organs. In this grant, we will explore the possibility of inhibiting autophagy of endothelial cells as a means of reversing the endothelium's tumor promoting behavior to sensitize cancer cells to subsequent immunotherapy.

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