BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion

• DOI: 10.1126/scitranslmed.abn7336
• Publication Date: 2022-11-09T18:58:03Z
• Authors: In-Young Jung; Vivek Narayan; Sierra McDonald; Andrew J. Rech; Robert Bartoszek; Gwanui Hong; Megan M. Davis; Jun Xu; Alina C. Boesteanu; Julie S. Barber-R...; Gabriela Plesa; Simon F. Lacey; Julie K. Jadlowsky; Donald L. Siegel; Dana M. Hammill; Park F. Cho-Park; Shelley L. Berger; Naomi B. Haas; Joseph A. Fraietta
• Keywords: Male; 0301 basic medicine; Receptors, Steroid; Receptors, Thyroid Hormone; Nerve Tissue Proteins; CD8-Positive T-Lymphocytes; Immunotherapy, Adoptive; Article; 3. Good health; DNA-Binding Proteins; Mice; 03 medical and health sciences; Neoplasms; Cell Line, Tumor; Humans; Animals; Hepatitis A Virus Cellular Receptor 2; Transcription Factors

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1 , encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]–expressing CD8 + CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]–expressing CD8 + T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7 -dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)–driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3 + CD8 + and toward TCF1 + CD8 + to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.