Adaptive resistance in tumors to anti-PD-1 therapy through re-immunosuppression by upregulation of GPNMB expression.

Abstract

Acquired resistance to the antitumor activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in various types of cancers has increasingly been observed during treatment. To gain insight into the molecular mechanism underlying anti-PD-1 therapy resistance, we developed a mouse MC38 colon adenocarcinoma cell line that was made resistant to anti-PD-1 treatment through repeated in vivo selection. We compared the transcriptomic profiles of anti-PD-1 therapy-resistant and -sensitive tumors using RNA sequencing analysis. The immunosuppressive molecule transmembrane glycoprotein NMB (GPNMB) was significantly upregulated in resistant tumor cells, as determined using quantitative real-time polymerase chain reaction and immunofluorescence analyses. Furthermore, deletion of GPNMB in resistant cells successfully restored sensitivity to anti-PD-1 treatment in vivo. Collectively, our results indicate that tumors may develop resistance to anti-PD-1 therapy by upregulating their expression of the immunosuppressive molecule GPNMB. Furthermore, GPNMB is a potential, targetable biomarker for monitoring adaptive resistance to therapeutic PD-1 blockade, and identification of this immunosuppressive molecule may be a breakthrough for new therapies.

• Authors: Xiaoqing Xu, Kun Xie, Bingyu Li, Lijun Xu, Lei Huang, Yan Feng, Chenyu Pi, Jingming Zhang, Tao Huang, Ming Jiang, Hua Gu, Jianmin Fang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 101 Issue Pt B Pg. 108199 (Dec 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 34673297 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents
• Eye Proteins
• Gpnmb protein, mouse
• Membrane Glycoproteins
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Valerates
• Validol

Topics

• Adaptation, Physiological
• Adenocarcinoma (drug therapy, genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Eye Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Immunosuppression Therapy
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Neoplasms, Experimental
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Specific Pathogen-Free Organisms
• Tumor Microenvironment
• Up-Regulation
• Valerates