TY  - JOUR
AU  - Weisshaar, Nina
AU  - Wu, Jingxia
AU  - Ming, Yanan
AU  - Madi, Alaa Abdelghani Mohamed
AU  - Hotz-Wagenblatt, Agnes
AU  - Ma, Sicong
AU  - Mieg, Alessa
AU  - Hering, Marvin
AU  - Zettl, Ferdinand
AU  - Mohr, Kerstin
AU  - Schlimbach, Tilo
AU  - Ten Bosch, Nora
AU  - Hertel, Franziska
AU  - Müller, Lisann
AU  - Byren, Hannah
AU  - Wang, Mona
AU  - Borgers, Helena
AU  - Munz, Mareike
AU  - Schmitt, Lukas
AU  - van der Hoeven, Franciscus
AU  - Kloz, Ulrich
AU  - Carretero, Rafael
AU  - Schleußner, Nikolai
AU  - Jackstadt, Rene-Filip
AU  - Hofmann, Ilse
AU  - Cui, Guoliang
TI  - Rgs16 promotes antitumor CD8+ T cell exhaustion.
JO  - Science immunology
VL  - 7
IS  - 71
SN  - 2470-9468
CY  - Washington, DC
PB  - AAAS
M1  - DKFZ-2022-01105
SP  - eabh1873
PY  - 2022
N1  - #EA:D192#LA:D192# / HI-TRON
AB  - T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Tex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Tex 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 Tex cell survival in tumors and has implications for improving T cell-based immunotherapies.
LB  - PUB:(DE-HGF)16
C6  - pmid:35622904
DO  - DOI:10.1126/sciimmunol.abh1873
UR  - https://inrepo02.dkfz.de/record/180112
ER  -