Targeting regulator of G protein signaling 1 in tumor-specific T cells enhances their trafficking to breast cancer

Nat Immunol. 2021 Jul;22(7):865-879. doi: 10.1038/s41590-021-00939-9. Epub 2021 Jun 17.


Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Apoptosis
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Carcinoma, Ductal, Breast / immunology
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Ductal, Breast / therapy
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Chemotaxis, Leukocyte*
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Female
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Lymphocytes, Tumor-Infiltrating / transplantation
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Microscopy, Video
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / transplantation
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Time Factors
  • Time-Lapse Imaging
  • Tumor Cells, Cultured
  • Tumor Escape


  • Chemokines
  • RGS Proteins
  • RGS1 protein, human