Defining the role of microenvironmental ammonia in colorectal cancers

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Abstract: Colorectal cancer is a grave public health concern with only a 14% survival rate for Stage IV diagnosis, and few viable treatment options. Colon tumors are composed of a cadre of cells and the interplay between these cells is critical for tumor growth. Previous work shows that the initial immune-tumor dynamic is robustly anti- tumor, but that this anti-tumor response is attenuated as tumors progress. Immunotherapies that re-activate the anti-tumor response are currently widely used in many cancers. Although colon tumors have a robust immune infiltrate, immunotherapies have largely failed for unclear reasons. Further, cancer cells are known to reprogram cellular metabolism to meet their proliferative needs. Cancer cell proliferation produces metabolic waste products that can be re-purposed to maintain cellular bioenergetic needs. However, it is clear that the vast majority of the metabolic byproducts accumulate in the tumor microenvironment. There is a critical gap regarding how metabolic waste products interact with the immune infiltrates. My preliminary data demonstrates that KRAS mutant colon tumors have an increase in ammonia waste that accumulates in the tumor microenvironment. Moreover, my preliminary data shows that T cell proliferation and anti-tumor response is significantly inhibited at biologically relevant concentrations that have been detected in colon tumors, while other cell types are largely unaffected. I have also shown that chemical ammonia detoxification reduces tumor growth in a T cell dependent manner. This suggests that ammonia waste contributes to the attenuated anti- tumor immune response commonly observed in colon cancer. data I hypothesize that increased microenvironmental ammonia in advanced cancers is central to maintaining an immunosuppressive state by altering T cell function. The long-term goal of this proposal is to understand how colorectal tumors modulate the microenvironment through metabolic products to decrease the effectiveness of the immune response. Understanding this will advance the development of immune-based therapeutic regimens. Based on these observations, the experimental focus of this proposal is on the regulatory role of tumor-generated ammonia on T cell function. Aim 1 will determine whether KRAS mutation is driving ammonia accumulation in advanced cancers. Aim 2 will explore how detoxifying ammonia in the tumor microenvironment increases the T cell immune response, using both genetic and chemical interventions. Preventing this negative hetero- cellular cross talk between the tumor and T cells may improve the efficacy of immunotherapy approaches in colorectal cancer. Importantly, pursuing the aims specified in this proposal will provide rigorous scientific and clinical training at a highly ranked and well supported institution. This type of institutional, facility, and mentor support will further my path towards a career as a physician scientist with an active oncology laboratory.