Comprehensive analysis of cutaneous and uveal melanoma liver metastases.

Autor:	Hoefsmit EP; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Rozeman EA; Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Van TM; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Dimitriadis P; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Krijgsman O; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Conway JW; Melanoma Institute Australia, North Sydney, New South Wales, Australia., Pires da Silva I; Melanoma Institute Australia, North Sydney, New South Wales, Australia., van der Wal JE; Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Ketelaars SLC; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Bresser K; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Broeks A; Core Facility and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands., Kerkhoven RM; NKI Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands., Reeves JW; NanoString Technologies Inc, Seattle, Washington, USA., Warren S; NanoString Technologies Inc, Seattle, Washington, USA., Kvistborg P; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Scolyer RA; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia.; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia., Kapiteijn EW; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Peeper DS; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Long GV; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Royal North Shore Hospital, Melanoma Institute Australia, and The University of Sydney, Wollstonecraft, New South Wales, Australia., Schumacher TNM; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Blank CU; Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands c.blank@nki.nl.; Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Dec; Vol. 8 (2).
DOI:	10.1136/jitc-2020-001501
Abstrakt:	Background: The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Methods: Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Results: Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. Conclusions: While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered. Competing Interests: Competing interests: EAR received travel support from NanoString Technologies and MSD. TMV received travel support from BMS. JWR is an employee and stockholder of Nanostring Technologies. SW is an employee and stockholder of Nanostring Technologies. PK reports receiving commercial research grants from Bristol-Myers Squibb and Merck and is a consultant/advisory board member for Neon Therapeutics and Personalis. RAS reports having received fees for professional services from Qbiotics, Novartis, MSD Sharp & Dohme, NeraCare, AMGEN, Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline and us supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant and NHMRC Practitioner Fellowship. Support from the Ainsworth Foundation, ClearBRIDGE Foundation and colleagues at Melanoma Institute Australia and Royal Prince Alfred Hospital are also gratefully acknowledged. EK has served as a consultant advisor for BMS, Novartis, Roche, Merck, Amgen, Pierre-Fabre, EISAI, Bayer, Genzyme-Sanofi for which the institution (LUMC) received funding, and received research grants from BMS. DSP is cofounder, shareholder and advisor of Immagene B.V. GVL is consultant advisor for Aduro, Amgen, Bristol-Myers Squibb, Highlight Therapeutics S.L., Mass-Array, Merck, MSD, Novartis, OncoSec Medical, Pierre Fabre, Roche, QBiotics, Skyline DX and Sandoz. TS has served as a consultant advisor for Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, and Scenic Biotech; is recipient of grant and research support from MSD, BMS, and Merck KGaA; is a stockholder in AIMM Therapeutics, Allogene Therapeutics, Merus, Neogene Therapeutics, and Neon Therapeutics; and is a venture partner at Third Rock Ventures. CB reports personal fees as a consultant advisor for BMS, MSD, Novartis, Lilly, Pfizer, GSK, GenMab, Pierre Fabre and Third Rock Venture for which the institute (Netherlands Cancer Institute) received payments, has received research grants from BMS, Novartis, and NanoString Technologies all paid to the institute (Netherlands Cancer Institute), and is cofounder of Immagene B.V. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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