Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition

Jenny H. Lee, Elena Shklovskaya, Su Yin Lim, Matteo S. Carlino, Alexander M. Menzies, Ashleigh Stewart, Bernadette Pedersen, Malama Irvine, Sara Alavi, Jean Y. H. Yang, Dario Strbenac, Robyn P. M. Saw, John F. Thompson, James S. Wilmott, Richard A. Scolyer, Georgina V. Long, Richard F. Kefford and Helen Rizos ()
Additional contact information
Jenny H. Lee: Macquarie University
Elena Shklovskaya: Macquarie University
Su Yin Lim: Macquarie University
Matteo S. Carlino: Melanoma Institute Australia
Alexander M. Menzies: Melanoma Institute Australia
Ashleigh Stewart: Macquarie University
Bernadette Pedersen: Macquarie University
Malama Irvine: Macquarie University
Sara Alavi: Melanoma Institute Australia
Jean Y. H. Yang: School of Mathematics and Statistics, The University of Sydney
Dario Strbenac: School of Mathematics and Statistics, The University of Sydney
Robyn P. M. Saw: Melanoma Institute Australia
John F. Thompson: Melanoma Institute Australia
James S. Wilmott: Melanoma Institute Australia
Richard A. Scolyer: Melanoma Institute Australia
Georgina V. Long: Melanoma Institute Australia
Richard F. Kefford: Macquarie University
Helen Rizos: Macquarie University

Nature Communications, 2020, vol. 11, issue 1, 1-12

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 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.

Date: 2020
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DOI: 10.1038/s41467-020-15726-7

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