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Defining the Role of Nr4a Transcription Factors in CD8+ T Cell Exhaustion Using a Murine CAR T Cell Tumor Model


In cancer immunotherapy, T cells expressing chimeric antigen receptors (CAR T) targeting human CD19 (hCD19) antigen have exhibited impressive clinical efficacy against B cell leukemias and lymphomas. However, CAR T cells have been less effective against solid tumors, in part because they enter a hyporesponsive (“exhausted” or “dysfunctional”) state that is triggered by chronic antigen stimulation and characterized by upregulation of several inhibitory receptors and loss of effector function. To identify transcriptional and other regulators contributing to the diminished function of CAR T cells in solid tumors, we developed a mouse model in which recipient mice bearing murine melanoma tumors expressing hCD19 antigen were adoptively transferred with hCD19-reactive CAR T cells. We show that CD8+ CAR-expressing tumor-infiltrating lymphocytes (TILs) and endogenous TILs with low effector function and high expression of inhibitory surface receptors PD-1 and TIM3 exhibit similar profiles of gene expression and chromatin accessibility, associated with secondary activation of the three Nr4a (Nuclear Receptor Subfamily 4 Group A) transcription factors Nr4a1 (Nur77), Nr4a2 (Nurr1) and Nr4a3 (Nor1) by the initiating transcription factor NFAT (nuclear factor of activated T cells). Through a similar comparison of data from human CD8+ TILs and viral antigen specific CD8+ T cells from humans chronically-infected with HIV, we observed high expression of Nr4a transcription factors and enrichment of Nr4a binding motifs in uniquely accessible chromatin regions. Treatment of tumor-bearing mice with CAR T cells lacking all three Nr4a transcription factors (Nr4a TKO) resulted in tumor regression and prolonged survival compared to mice adoptively transferred with Nr4a-sufficient (WT) CAR T cells. Nr4a TKO CAR TILs displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a TKO CAR TILs compared to wild type were enriched for binding motifs for NFB and AP-1, transcription factors classically involved in T cell activation. Our data identify Nr4a transcription factors as major players in the cell-intrinsic program of T cell hyporesponsiveness and point to Nr4a inhibition as a promising strategy for cancer immunotherapy.

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