Tumor cell-intrinsic MHC class II expression as a determinant of immunotherapy responsiveness in an orthotopic mouse model of non-small cell lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide and the second most common cancer among both men and women in the United States. Immunotherapy regimens that disrupt the inhibitory PD-1/PD-L1 axis have recently emerged as promising treatments that can unleash anti-tumor immunity against a wide range of cancers, including a subset of lung cancers. How these therapies elicit potent anti-tumor immunity remains controversial, with markers for immunotherapy-sensitivity still an active area of investigation. To study determinants of lung cancer growth in vivo we studied two orthotopic mouse models of non-small cell lung cancer (NSCLC). These Kras-mutant tumor lines dramatically differ in their response to immunotherapy: CMT167 tumor cells are exquisitely susceptible to PD-1/PD-L1 targeted immunotherapy whereas LLC tumor cells are immunotherapy-resistant. Immunotherapy-sensitive cells showed induction of the MHC class II antigen processing and presentation pathway in vitro and in vivo, and were capable of stimulating CD4 T cells directly in ex vivo co-culture. To study the impact of tumor cell-intrinsic MHC class II induction, we used RNA interference to knockdown CIITA, a transcriptional inducer of the MHC class II pathway. CIITA knockdown in immunotherapy-sensitive cells impaired the induction of tumor cell-intrinsic MHC class II in vitro and abrogated CD4 T cell stimulation in co-culture. CIITA knockdown further converted tumors from immunotherapy-sensitive to immunotherapy-resistant. These studies identify tumor cell-intrinsic expression of MHC class II as a potential direct target for CD4 T cell recognition that may promote sensitivity to PD-1/PD-L1 blockade.