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

Baojun Wang; Bo Jiang; Lin Du; Wenyuan Chen; Qing Zhang; Wei Chen; Meng Ding; Wenmin Cao; Jie Gao; Yongming Deng; Yao Fu; Yan Li; Yonglong Xiao; Wenli Diao; Hongqian Guo

doi:10.1080/2162402X.2023.2279800

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

Oncoimmunology. 2023 Nov 20;12(1):2279800. doi: 10.1080/2162402X.2023.2279800. eCollection 2023.

Authors

Baojun Wang^{1

2}, Bo Jiang², Lin Du³, Wenyuan Chen¹, Qing Zhang², Wei Chen², Meng Ding², Wenmin Cao², Jie Gao², Yongming Deng², Yao Fu⁴, Yan Li⁵, Yonglong Xiao⁵, Wenli Diao², Hongqian Guo^{1

2}

Affiliations

¹ Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
² Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
³ Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Southeast University Medical School, Nanjing, Jiangsu, China.
⁴ Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
⁵ Department of Respiratory and Critical Care Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Abstract

Background: Non-responsiveness is a major barrier in current cancer immune checkpoint blockade therapies, and the mechanism has not been elucidated yet. Therefore, it is necessary to discover the mechanism and biomarkers of tumor immunotherapeutic resistance.

Methods: Bioinformatics analysis was performed based on CD8⁺ T cell infiltration in multiple tumor databases to screen out genes related to anti-tumor immunity. Associations between Regulator of G-protein signaling 1 (RGS1) and IFNγ-STAT1 signaling, and MHCI antigen presentation pathway were examined by RT-qPCR, western blotting, and flow cytometry. The modulatory mechanisms of RGS1 were investigated via CHIP-qPCR and dual-luciferase assay. The clinical and therapeutic implications of RGS1 were comprehensively investigated using tumor cell lines, mouse models, and clinical samples receiving immunotherapy.

Results: RGS1 was identified as the highest gene positively correlated with immunogenicity among RGS family. Inhibition of RGS1 in neoplastic cells dampened anti-tumor immune response and elicited resistance to immunotherapy in both renal and lung murine subcutaneous tumors. Mechanistically, RGS1 enhanced the binding of activating transcription factor 3 (ATF3) to the promoter of interferon gamma receptor 1 (IFNGR1), activated STAT1 and the subsequent expression of IFNγ-inducible genes, especially CXCL9 and MHC class I (MHCI), thereby influenced CD8⁺ T cell infiltration and antigen presentation and processing. Clinically, lower expression level of RGS1 was associated with resistance of PD1 inhibition therapy and shortened progression-free survival among 21 NSCLC patients receiving immunotherapy.

Conclusions: Together, these findings uncover a novel mechanism that elicits immunotherapy resistance and highlight the function of tumor-intrinsic RGS1, which brings new insights for future strategies to sensitize anti-PD1 immunotherapy.

Keywords: IFNγ signaling; NSCLC; RCC; RGS1; immunotherapy.

MeSH terms

Activating Transcription Factor 3
Animals
Antigen Presentation
Carcinoma, Non-Small-Cell Lung*
Humans
Immunotherapy
Lung Neoplasms*
Mice
RGS Proteins*

Substances

Activating Transcription Factor 3
RGS1 protein, human
RGS Proteins
ATF3 protein, human

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (81972388, 82173160 and 82002681) and the Natural Science Foundation of Jiangsu Province (BK20200123).