期刊
SCIENCE IMMUNOLOGY
卷 7, 期 71, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abh1873
关键词
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资金
- DKFZ/Bayer Innovation Alliance
- CRI Lloyd J. Old STAR Award [3914]
- Helmholtz Young Investigator Award [VH-NG-1113]
- EMBO Young Investigator Award
- German Research Foundation (DFG) [CU375/5-1, CU375/5-2, CU375/7-1, CU375/9-1, 259332240/RTG2099]
- German Cancer Aid Foundation [70113343, 70114224]
- Hector Foundation [M20102]
- ERC Consolidator Award [101045416]
- Helmholtz International Graduate School
- Helmholtz Zukunftsthema Ageing and Metabolic Programming (AMPro) [ZT0026]
- HI-TRON Kick-Start Seed Funding [HITR-2021-08]
- European Research Council (ERC) [101045416] Funding Source: European Research Council (ERC)
This study reveals Rgs16 as an inhibitor of T-ex cell survival in tumors and its interaction with Erk1 impacting the antitumor functions of CD8(+) T cells.
T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (T-ex) cell differentiation are known, comparatively little is known about the regulators of T-ex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T-ex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16(+)CD8(+) tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8(+) T cell apoptosis and promoted antitumor effector functions of CD8(+) T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8(+) T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8(+) TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8(+) T cells. RGS16 mRNA expression levels in CD8(+) TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T-ex cell survival in tumors and has implications for improving T cell-based immunotherapies.
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