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, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

152 Citations (Scopus)
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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.

Original languageEnglish
Article number1897
Pages (from-to)1-12
Number of pages12
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • Melanoma
  • Immuntherapies
  • Mhc class I


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