Rgs16 promotes antitumor CD8+ T cell exhaustion.

Abstract

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.

• Authors: Nina Weisshaar, Jingxia Wu, Yanan Ming, Alaa Madi, Agnes Hotz-Wagenblatt, Sicong Ma, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Tilo Schlimbach, Nora Ten Bosch, Franziska Hertel, Lisann Müller, Hannah Byren, Mona Wang, Helena Borgers, Mareike Munz, Lukas Schmitt, Franciscus van der Hoeven, Ulrich Kloz, Rafael Carretero, Nikolai Schleußner, Rene-Filip Jackstadt, Ilse Hofmann, Guoliang Cui
• Journal: Science immunology (Sci Immunol) Vol. 7 Issue 71 Pg. eabh1873 (05 27 2022) ISSN: 2470-9468 [Electronic] United States
• PMID: 35622904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Programmed Cell Death 1 Receptor
• RGS Proteins
• RGS16 protein

Topics

• Animals
• CD8-Positive T-Lymphocytes
• Cell Differentiation
• Humans
• Immunotherapy
• Lymphocytes, Tumor-Infiltrating
• Mice
• Programmed Cell Death 1 Receptor
• RGS Proteins (immunology)