期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 25, 页码 12410-12415出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1905675116
关键词
TOX; TOX2; NR4A; NFAT; CD8(+) T cell hyporesponsiveness
资金
- NIH [AI108651, AI140095, OD016262, RR027366, GM007752]
- Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH [AI109842, AI040127]
- American Association for Cancer Research-Genentech Immuno-oncology Research Fellowship [18-40-18-SEO]
- Donald J. Gogel Cancer Research Irvington Fellowship
- PhRMA Foundation Paul Calabresi Medical Student Research Fellowship
- University of California Institute for Mexico
- El Consejo Nacional de Ciencia y Tecnologia (UCMEXUS/CONACYT)
- NATIONAL CANCER INSTITUTE [ZIABC011633] Funding Source: NIH RePORTER
T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive (exhausted or dysfunctional) within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8(+) T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8(+) CAR(+)PD-1(high) TIM3(high) (exhausted) tumor-infiltrating lymphocytes (CAR TIL5), and CAR TIL5 deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TIL5 in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TIL5, Tox DKO CAR TIL5 show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation-associated nuclear factor kappa B (NF kappa B) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8(+) T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.
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