T cells become dysfunctional during cancer, a state termed T cell exhaustion, which limits tumor control by the immune system. Immune checkpoint inhibitors (ICI) are designed to reinvigorate antitumor T cell immunity, but only a fraction of cancer patients respond to these drugs. A newly discovered subset of CD8 T cells, known as stem-like CD8 T cells, mediates ICI-induced antitumor T cell immunity in mice and positively correlates with the ICI-induced response in cancer patients. Thus, enhancing the stem-like CD8 T cell response represents a potential strategy for improving the ICI efficacy.

Renal cell carcinoma (RCC), a prevale...

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T cells become dysfunctional during cancer, a state termed T cell exhaustion, which limits tumor control by the immune system. Immune checkpoint inhibitors (ICI) are designed to reinvigorate antitumor T cell immunity, but only a fraction of cancer patients respond to these drugs. A newly discovered subset of CD8 T cells, known as stem-like CD8 T cells, mediates ICI-induced antitumor T cell immunity in mice and positively correlates with the ICI-induced response in cancer patients. Thus, enhancing the stem-like CD8 T cell response represents a potential strategy for improving the ICI efficacy.

Renal cell carcinoma (RCC), a prevalent cancer in Texas, is only modestly responsive to ICIs. Why RCC is not more responsive is unclear; however, stem-like CD8 T cells have been identified in RCC tumors, suggesting that these cells may play a role in the anti-tumor response and could be further stimulated to enhance immunity. Using next-generation sequencing tools and genome editing technology, I previously characterized the transcriptional and epigenetic programs governing stem-like CD8 T cell differentiation.

As an independent investigator in the Kidney Cancer Program at UT Southwestern, my goal is to harness stem-like CD8 T cells to improve the efficacy of ICIs against RCC.HIF2α inhibitors are being evaluated in RCC patients. My preliminary data suggests that HIF inhibition may enhance stem-like CD8 T cells. In Aim 1, I will define the stem-like CD8 T cell response during HIF2α antagonism and PD1 blockade in RCC. In general, antitumor T cell immunity is tightly regulated by the tumor microenvironment, thus in Aim 2, I will determine the effect of myeloid cells in the RCC tumor microenvironment on the differentiation and function of stem-like CD8 T cells.

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