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

•A mouse colon adenocarcinoma cell line resistant to anti-PD1 therapy was developed.•GPNMB was significantly upregulated in anti-PD1 therapy-resistant tumor cells.•GPNMB deletion in resistant cells restored sensitivity to anti-PD1 therapy in vivo.•Tumors may resist anti-PD1 therapy by upregulating the immunosuppressive GPNMB. 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.