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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:
List of abbreviations
| RGS1 | = | Regulator of G-protein signaling 1 |
| ATF3 | = | Activating Transcription actor 3 |
| IFNGR1 | = | Interferon Gamma Receptor 1 |
| TILs | = | Tumor-infiltrating lymphocytes |
| PD-L1 | = | Programmed death ligand 1 |
| ICB | = | Immune checkpoint blockade |
| ccRCC | = | clear cell Renal Cell Carcinoma |
| NSCLC | = | Non-small cell lung cancer |
| GPCR | = | G-protein coupled receptor |
| CTLs | = | Cytotoxic T lymphocytes |
| CHIP | = | Chromatin immunoprecipitation |
| GSEA | = | Gene Set Enrichment Analysis |
| TCGA | = | The Cancer Genome Atlas |
Acknowledgments
We thank Prof. H. Tang (Shandong First Medical University, China) and Prof. J. Li (Nanjing University, China) for the donation of Transgenic OT-I mice and mouse lentiviral vector encoding OVA, respectively. In addition, we also thank Prof. YC. Xu (Zhejiang University, China) for his suggestions on the article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Authors’ contributions
H.G., B.W., and W.D. devised and coordinated the project. B.W. performed all the experiments with help from B.J. and L.D.; W.D., Q.Z. and Y.W. performed bioinformatics analyses. B.J., W.C., M.D. and W.C. performed experiments with the Renca/LLC tumor models. J.G., Y.F. and Y.D. collected clinical samples and performed IHC and IF analyses. B.J., W.D., and H.G. wrote the manuscript. All authors revised the manuscript.
Consent for publication
Patients in the study were in compliance with informed consent policy and gave permission for publication.
Ethics approval and consent to participate
The study protocol was under the approval of the Institutional Review Board of Nanjing Drum Tower Hospital (approval 2017-147-01). The collection of all tissue samples was in compliance with informed consent policy.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2279800