Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

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 IFNγ response genes. Upregulation of IFNγ 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 IFNγ 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. Tumor tissue samples from pre- and post-immunotherapy treatment timepoints were obtained from patients with NSCLC patients treated with PD-1 blockade (n = 29). All samples were processed as FFPE. 13 samples were obtained prior to initiation of therapy (pre-treatment) and 29 samples were obtained at time of acquired resistance (post-treatment). The RNA samples quantification was performed using the Affymetrix Clariom D Pico assay.