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- Title
Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.
- Authors
Lee, Jenny H.; Shklovskaya, Elena; Lim, Su Yin; Carlino, Matteo S.; Menzies, Alexander M.; Stewart, Ashleigh; Pedersen, Bernadette; Irvine, Malama; Alavi, Sara; Yang, Jean Y. H.; Strbenac, Dario; Saw, Robyn P. M.; Thompson, John F.; Wilmott, James S.; Scolyer, Richard A.; Long, Georgina V.; Kefford, Richard F.; Rizos, Helen
- 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. A significant proportion of patients develop innate or acquired resistance to immune checkpoint inhibitors. Here, the authors show that resistance to anti-PD-1 blockade is associated with TGF-beta driven major histocompatibility complex I (MHCI) down-regulation and a de-differentiated phenotype in melanoma patients.
- Subjects
IMMUNE checkpoint inhibitors; MAJOR histocompatibility complex; MELANOMA; DOWNREGULATION; NATURAL immunity; PROGRAMMED cell death 1 receptors
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-15726-7