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

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

Nature communications, 2020-04, Vol.11 (1), p.1897-1897, Article 1897 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition
Autor: 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
Assuntos: Adult ; Aged ; Aged, 80 and over ; Cell Differentiation ; Cell Line, Tumor ; Differentiation ; Down-Regulation ; Drug Resistance, Neoplasm - genetics ; Female ; Flow cytometry ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genotype & phenotype ; Heterogeneity ; Histocompatibility Antigens Class I - genetics ; Histocompatibility Antigens Class I - metabolism ; Humans ; Immune checkpoint inhibitors ; Immunosuppressive agents ; Immunotherapy ; Inhibitors ; Lymphocytes T ; Major histocompatibility complex ; Male ; Melanoma ; Melanoma - genetics ; Melanoma - metabolism ; Melanoma - pathology ; Middle Aged ; PD-1 protein ; Performance prediction ; Phenotypes ; Programmed Cell Death 1 Receptor - drug effects ; Programmed Cell Death 1 Receptor - metabolism ; Ribonucleic acid ; RNA ; Signal transduction ; Signatures ; Transcription ; Transcriptome ; Transcriptomics ; Tumor Microenvironment - drug effects ; Tumors
É parte de: Nature communications, 2020-04, Vol.11 (1), p.1897-1897, Article 1897
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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 MITF /AXL de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITF /AXL ) 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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