PD-L1 Expression Increased by IFN-γ Via JAK2-STAT1 Signaling and Predicts a Poor Survival in Colorectal Cancer

Overview

Journal Oncol Lett

Specialty Oncology

Date 2020 Jul 30

PMID 32724352

Citations 47

Authors

Tiancheng Zhao

Yezhou Li

Jiayu Zhang

Bin Zhang

Affiliations

Soon will be listed here.

Abstract

PD-L1 inhibitors are widely used in tumor immunotherapy, but their mechanism in colorectal cancer remains unclear. The present study aimed to investigate the mechanisms underlying programmed death ligand 1 (PD-L1) regulation via the interferon-γ (IFN-γ)/janus kinase (JAK)/STAT signaling pathway, and its prognostic value in patients with colorectal cancer (CRC). A cohort of 181 patients were recruited to determine the association between PD-L1 expression and CRC prognosis; the patients were newly diagnosed with colorectal adenocarcinoma and had also undergone a physical tumorectomy. Immunohistochemical staining and survival analysis were used to evaluate the predictive value of PD-L1 protein expression in CRC. Gene set enrichment analysis, RT-qPCR and western blotting, etc were performed to confirm that PD-L1 is regulated by the IFN-γ/JAK/STAT signaling pathway. PD-L1 up-regulation was more frequently observed in patients with larger tumors, positive vascular or lymphatic infiltration and a poorly differentiated stage in addition to being associated with a poor survival in patients with CRC. Following the stimulation with IFN-γ, PD-L1 expression levels were revealed to be increased via the JAK2/STAT1 signaling pathway. In conclusion, the findings of the present study indicated that the expression levels of PD-L1 may be associated with a poor prognosis in patients with CRC. In addition, the results suggested that the IFN-γ-mediated overexpression of PD-L1 in CRC cells may be regulated by the JAK2/STAT1 signaling pathway.

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References

Imai D, Yoshizumi T, Okano S, Itoh S, Ikegami T, Harada N . IFN-γ Promotes Epithelial-Mesenchymal Transition and the Expression of PD-L1 in Pancreatic Cancer. J Surg Res. 2019; 240:115-123. DOI: 10.1016/j.jss.2019.02.038. View

Valentini A, Di Pinto F, Cariola F, Guerra V, Giannelli G, Caruso M . PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments. Oncotarget. 2018; 9(9):8584-8596. PMC: 5823560. DOI: 10.18632/oncotarget.24196. View

Tapia Rico G, Townsend A, Broadbridge V, Price T . Targeted Therapies in Elderly Patients with Metastatic Colorectal Cancer: A Review of the Evidence. Drugs Aging. 2017; 34(3):173-189. DOI: 10.1007/s40266-017-0439-9. View

Gotthardt D, Putz E, Grundschober E, Prchal-Murphy M, Straka E, Kudweis P . STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion. Cancer Discov. 2016; 6(4):414-29. DOI: 10.1158/2159-8290.CD-15-0732. View

Concha-Benavente F, Srivastava R, Trivedi S, Lei Y, Chandran U, Seethala R . Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res. 2015; 76(5):1031-43. PMC: 4775348. DOI: 10.1158/0008-5472.CAN-15-2001. View

Bellucci R, Martin A, Bommarito D, Wang K, Hansen S, Freeman G . Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology. 2015; 4(6):e1008824. PMC: 4485824. DOI: 10.1080/2162402X.2015.1008824. View

Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K . KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2016; 45(D1):D353-D361. PMC: 5210567. DOI: 10.1093/nar/gkw1092. View

Carretero-Gonzalez A, Lora D, Ghanem I, Zugazagoitia J, Castellano D, Sepulveda J . Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. Oncotarget. 2018; 9(9):8706-8715. PMC: 5823578. DOI: 10.18632/oncotarget.24283. View

Sudoyo A, Kurniawan A, Kusumo G, Putra T, Rexana F, Yunus M . Increased CD8 Tumor Infiltrating Lymphocytes in Colorectal Cancer Microenvironment Supports an Adaptive Immune Resistance Mechanism of PD-L1 Expression. Asian Pac J Cancer Prev. 2019; 20(11):3421-3427. PMC: 7063011. DOI: 10.31557/APJCP.2019.20.11.3421. View

10.

Binefa G, Rodriguez-Moranta F, Teule A, Medina-Hayas M . Colorectal cancer: from prevention to personalized medicine. World J Gastroenterol. 2014; 20(22):6786-808. PMC: 4051918. DOI: 10.3748/wjg.v20.i22.6786. View

11.

Wu Y, Cao D, Qu L, Cao X, Jia Z, Zhao T . PD-1 and PD-L1 co-expression predicts favorable prognosis in gastric cancer. Oncotarget. 2017; 8(38):64066-64082. PMC: 5609984. DOI: 10.18632/oncotarget.19318. View

12.

Li Y, He M, Zhou Y, Yang C, Wei S, Bian X . The Prognostic and Clinicopathological Roles of PD-L1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis. Front Pharmacol. 2019; 10:139. PMC: 6403169. DOI: 10.3389/fphar.2019.00139. View

13.

Gao J, Aksoy B, Dogrusoz U, Dresdner G, Gross B, Sumer S . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269):pl1. PMC: 4160307. DOI: 10.1126/scisignal.2004088. View

14.

Nagtegaal I, Odze R, Klimstra D, Paradis V, Rugge M, Schirmacher P . The 2019 WHO classification of tumours of the digestive system. Histopathology. 2019; 76(2):182-188. PMC: 7003895. DOI: 10.1111/his.13975. View

15.

Liu R, Peng K, Yu Y, Liang L, Xu X, Li W . Prognostic Value of Immunoscore and PD-L1 Expression in Metastatic Colorectal Cancer Patients with Different RAS Status after Palliative Operation. Biomed Res Int. 2018; 2018:5920608. PMC: 5831827. DOI: 10.1155/2018/5920608. View

16.

Li S, Chen L, Jiang J . Role of programmed cell death ligand-1 expression on prognostic and overall survival of breast cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2019; 98(16):e15201. PMC: 6494364. DOI: 10.1097/MD.0000000000015201. View

17.

Yaghoubi N, Soltani A, Ghazvini K, Hassanian S, Hashemy S . PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother. 2018; 110:312-318. DOI: 10.1016/j.biopha.2018.11.105. View

18.

Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N . Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 99(19):12293-7. PMC: 129438. DOI: 10.1073/pnas.192461099. View

19.

Angell H, Lee J, Kim K, Kim K, Kim S, Park S . PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology. 2019; 8(2):e1544442. PMC: 6351089. DOI: 10.1080/2162402X.2018.1544442. View

20.

Meyer S . Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms. Hematol Oncol Clin North Am. 2017; 31(4):627-642. DOI: 10.1016/j.hoc.2017.04.003. View