NIH Reporter #1R37CA302926-01A1

Antigen immunodominance in regulation of anti-tumor CD8 T cell immunity and immunotherapy response

This award funds research to understand and therapeutically target antigen immunodominance in CD8 T cell responses to improve cancer immunotherapy outcomes, particularly in refractory cancers like pancreatic cancer.

Description

Cancer immunotherapies that activate CD8 T cells to kill cancer cells have revolutionized cancer treatment in the clinic. However, most patients still do not respond to these therapies and some cancer types, like pancreatic cancer, remain highly refractory. A better understanding of the factors regulating CD8 T cell responses against tumors is needed to inform improved immunotherapies that could benefit more patients. CD8 T cells recognize and kill cancer based on the expression of mutated proteins by cancer cells, called neoantigens. Cancer cells can express up to hundreds of neoantigens, eliciting responses from different populations of CD8 T cells. Our recent work revealed that CD8 T cells responding to different neoantigens compete in their effort to control tumors, limiting the overall breadth and effectiveness of the anti-tumor T cell response. Antigen immunodominance hierarchies form wherein CD8 T cells responding to one or a few dominant neoantigens saturate the response and suppress CD8 T cell expansion and effector differentiation against other subdominant neoantigens. We hypothesize that antigen immunodominance is a predictable and targetable phenomenon that restricts CD8 T cell immunity in cancer and that therapeutically circumventing antigen immunodominance could more optimally engage CD8 T cell immunity for improved tumor control. The proposed work will establish antigen immunodominance as a novel therapeutic axis for predicting, modulating, and exploiting CD8 T cell responses to cancer.

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