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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41467-020-15726-7
Journal or Publication Title: Nature Communications
Volume: 11
Number: 1
Date: 2020
Divisions: Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1038/s41467-020-15726-7
ISSN: 2041-1723
Date Deposited: 04 Jan 2021 03:09
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.

Creators:
Creators
Email
Lee, Jenny H.
UNSPECIFIED
Shklovskaya, Elena
UNSPECIFIED
Lim, Su Yin
UNSPECIFIED
Carlino, Matteo S.
UNSPECIFIED
Menzies, Alexander M.
UNSPECIFIED
Stewart, Ashleigh
UNSPECIFIED
Pedersen, Bernadette
UNSPECIFIED
Irvine, Malama
UNSPECIFIED
Alavi, Sara
UNSPECIFIED
Yang, Jean Y. H.
UNSPECIFIED
Strbenac, Dario
UNSPECIFIED
Saw, Robyn P. M.
UNSPECIFIED
Thompson, John F.
UNSPECIFIED
Wilmott, James S.
UNSPECIFIED
Scolyer, Richard A.
UNSPECIFIED
Long, Georgina V.
UNSPECIFIED
Kefford, Richard F.
UNSPECIFIED
Rizos, Helen
UNSPECIFIED
Last Modified: 04 Jan 2021 03:09
URI: https://eprints.centenary.org.au/id/eprint/754

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