Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer

Despite the established use of immune checkpoint inhibitors to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and approximately 50% of patients whose tumors respond eventually develop acquired resistance. To identify novel drivers of acquired resistance, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed acquired resistance to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNɣ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia activated pro-drug delayed acquired resistance to immune checkpoint inhibitors in murine Msh2 KO tumors. Thus, this work provides rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.