Clinical and molecular features of acquired resistance to immunotherapy [RNA-seq]
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFN? response genes. Upregulation of IFN? response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFN? treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance. Overall design: The molecular changes on acquired resistance (AR) to anti-PD1 were examined using CT26 murine model system. To model acquired resistance, persistent viable CT26 cells following anti-PD-1 treatment were excised, cultured in vitro, and reimplanted in mice. This process was repeated for several passages until CT26 tumors were no longer responsive to anti-PD-1 antibody therapy. Bulk RNA-seq was performed on the ICB-resistant cancer cell lines derived from tumors from the 2nd round (n=2) and 4th round (n=4) of in vivo passage and compared against the ICB-sensitive parental cell line (n=3). Examination of mRNA levels from ICB-sensitive parental cell line (n=3) and anti-PD1 resistant cancer cell lines derived from tumors from the 2nd round (n=2) and 4th round (n=4) of in vivo passage, with or without in vitro IFN? stimulation.