Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY T cells responding to cancer develop a hyporesponsive phenotype, characterized by high levels of inhibitory receptor expression, low cytokine production, and a failure to control tumor growth. We have previously identified a transcriptional program induced by persistent antigen stimulation that was shared by mouse and human T cells responding to chronic viral infections and tumors. We linked this program to activation of the Nuclear Receptor Subfamily 4 Group A (NR4A) transcription factors (TFs), which are potently induced during chronic stimulation. We also identified NR4A-sensitive regulatory elements that became accessible in T cells responding to chronic viral infection and tumors. We found that NR4A TFs concomitantly promoted inhibitory receptor expression and limited cytokine production, leading to an exhausted T cell state that reduced chimeric antigen receptor expressing T (CAR-T) cell activity against solid tumors. CAR-T cells engineered to lack all three NR4A TFs differentiated to a unique population with potent anti-tumor activity compared to wild-type T cells. We connected this improved function to increased expression and activity of basic leucine zipper (bZIP) TFs in NR4A-deficient T cells than in wild-type. In new preliminary studies, we found that CAR-T cells with a partial loss of NR4A TFs also provided better protection than wild-type CAR-T cells, but had a unique “exhaustion resistant” phenotype that are poised for effector function and have increased potential for long term survival. In this application, we will test the hypothesis that NR4A and bZIP TFs can be “tuned” to control the transcriptional programs and function of “exhaustion resistant” CAR-T cells in tumors. In Aim 1, we will determine the impact of therapeutic interventions, using antibodies or small molecules, on the function and survival of “exhaustion resistant” CAR-T cells. In Aim 2, we will determine the contribution of NR4A regulated bZIP TFs to the function of NR4A-deficient CAR-T cells and their effects on transcriptional programs in “exhaustion resistant” CAR-T cells. In Aim 3, we will define the effects of NR4A TFs on bZIP TF activity at regulatory elements and identify chromatin associated co- factors that may be targeted to control the function of “exhaustion resistant” CAR-T cells. The expected outcome of our proposed studies is a comprehensive understanding of the effects of NR4A and bZIP TFs on CAR-T cells in tumors, through which we will identify practical strategies to “tune” the function of CAR-T cells for therapeutic benefit by controlling transcriptional programs.
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