Drugs that target TGFß signaling pathways may be effective future therapeutic strategies for melanoma patients

April 27, 2020


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 MITFlow/AXLhigh de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITFlow/AXLhigh) 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.


Lee, J. H., Shklovskaya, E., Lim, S. Y., Carlino, M. S., Menzies, A. M., Stewart, A., … Rizos, H. (2020). Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nature Communications11(1). doi: 10.1038/s41467-020-15726-7


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