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Tumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis

Baojun Wang1,2, Bo Jiang2, Lin Du3

  • 1Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Oncoimmunology
|January 24, 2024
PubMed
Abstract

Insights

Regulator of G-protein signaling 1 (RGS1) drives anti-tumor immunity and immunotherapy response. Inhibiting RGS1 causes resistance to cancer treatments like anti-PD1 therapy, suggesting RGS1 as a potential therapeutic target.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cancer immune checkpoint blockade therapies face non-responsiveness challenges.
  • Understanding tumor immunotherapeutic resistance mechanisms and biomarkers is crucial.

Purpose of the Study:

  • To identify genes associated with anti-tumor immunity.
  • To elucidate the role of Regulator of G-protein signaling 1 (RGS1) in immunotherapy resistance.
  • To explore RGS1 as a potential biomarker and therapeutic target.

Main Methods:

  • Bioinformatics analysis of CD8+ T cell infiltration in tumor databases.
  • RT-qPCR, western blotting, and flow cytometry to assess RGS1 function.
  • CHIP-qPCR and dual-luciferase assays to investigate RGS1 mechanisms.
  • In vivo studies using murine models and analysis of clinical samples from patients receiving immunotherapy.

Main Results:

  • RGS1 was identified as a key gene positively correlated with immunogenicity.
  • RGS1 inhibition in tumor cells led to dampened anti-tumor immunity and immunotherapy resistance in murine models.
  • RGS1 enhances IFNγ-STAT1 signaling and MHC class I presentation by modulating ATF3 binding to IFNGR1.
  • Lower RGS1 expression correlated with resistance to PD1 inhibition and shorter progression-free survival in NSCLC patients.

Conclusions:

  • RGS1 plays a critical role in tumor-intrinsic anti-tumor immunity.
  • RGS1 is a novel mechanism contributing to immunotherapy resistance.
  • Targeting RGS1 may offer new strategies to enhance anti-PD1 immunotherapy efficacy.
Keywords:
IFNγ signalingNSCLCRCCRGS1immunotherapy

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