Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition
Jenny Lee, Elena Shklovskaya, Su Yin Lim, Matteo S. Carlino, Alexander M. Menzies, Ashleigh Stewart, Bernadette Pedersen, Malama Irvine, Sara Alavi, Jean Yang, Dario Strbenac, Robyn P.M. Saw, John F. Thompson, James S. Wilmott, Richard A. Scolyer, Georgina V. Long, Richard Kefford, Helen Rizos
Abstract
Abstract Transcriptomic signatures designed to predict melanoma patient responses to PD-1 blockade have been reported but rarely validated. We now show that intra-patient heterogeneity of tumor responses to PD-1 inhibition limit the predictive performance of these signatures. We reasoned that resistance mechanisms will reflect the tumor microenvironment, and thus we examined PD-1 inhibitor resistance relative to T-cell activity in 94 melanoma tumors collected at baseline and at time of PD-1 inhibitor progression. Tumors were analyzed using RNA sequencing and flow cytometry, and validated functionally. These analyses confirm that major histocompatibility complex (MHC) class I downregulation is a hallmark of resistance to PD-1 inhibitors and is associated with the MITF low /AXL high de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITF low /AXL high ) and contributes to MHC class I downregulation in melanoma. Combinations of anti-PD-1 with drugs that target the TGFß signaling pathway and/or which reverse melanoma de-differentiation may be effective future therapeutic strategies.