Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance

Felicity Newell; Ines Pires da Silva; Peter A Johansson; Alexander M Menzies; James S Wilmott; Venkateswar Addala; Matteo S Carlino; Helen Rizos; Katia Nones; Jarem J Edwards; Vanessa Lakis; Stephen H Kazakoff; Pamela Mukhopadhyay; Peter M Ferguson; Conrad Leonard; Lambros T Koufariotis; Scott Wood; Christian U Blank; John F Thompson; Andrew J Spillane; Robyn P M Saw; Kerwin F Shannon; John V Pearson; Graham J Mann; Nicholas K Hayward; Richard A Scolyer; Nicola Waddell; Georgina V Long

doi:10.1016/j.ccell.2021.11.012

Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance

Cancer Cell. 2022 Jan 10;40(1):88-102.e7. doi: 10.1016/j.ccell.2021.11.012. Epub 2021 Dec 23.

Authors

Felicity Newell¹, Ines Pires da Silva², Peter A Johansson¹, Alexander M Menzies³, James S Wilmott⁴, Venkateswar Addala⁵, Matteo S Carlino⁶, Helen Rizos⁷, Katia Nones¹, Jarem J Edwards⁴, Vanessa Lakis¹, Stephen H Kazakoff¹, Pamela Mukhopadhyay¹, Peter M Ferguson⁸, Conrad Leonard¹, Lambros T Koufariotis¹, Scott Wood¹, Christian U Blank⁹, John F Thompson¹⁰, Andrew J Spillane¹¹, Robyn P M Saw¹⁰, Kerwin F Shannon¹², John V Pearson¹, Graham J Mann¹³, Nicholas K Hayward¹, Richard A Scolyer¹⁴, Nicola Waddell⁵, Georgina V Long¹⁵

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Cancer Centre, Blacktown Hospital, Sydney, NSW 2148, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Mater Hospital, Sydney, NSW 2060, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.
⁶ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia.
⁷ Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, NSW 2109, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Camperdown, NSW 2050, Australia.
⁹ Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Mater Hospital, Sydney, NSW 2060, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
¹¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Mater Hospital, Sydney, NSW 2060, Australia.
¹² Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Mater Hospital, Sydney, NSW 2060, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
¹³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; John Curtin School of Medical Research, Australian National University, ACT 2601, Australia.
¹⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Camperdown, NSW 2050, Australia.
¹⁵ Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Mater Hospital, Sydney, NSW 2060, Australia. Electronic address: georgina.long@melanoma.org.au.

PMID: 34951955
DOI: 10.1016/j.ccell.2021.11.012

Abstract

We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.

Keywords: RNAseq; anti-CTLA-4; anti-PD-1; immunotherapy; interferon-γ; melanoma; methylation; mutation burden; resistance; targeted therapy; treatment; whole genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Immunological / therapeutic use*
B7-H1 Antigen / immunology
Biomarkers, Tumor / genetics
CTLA-4 Antigen / immunology
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / immunology
Humans
Immunotherapy / methods
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Lung Neoplasms / immunology
Melanoma / drug therapy*
Melanoma / immunology
Melanoma, Cutaneous Malignant
Mutation / genetics
Skin Neoplasms / drug therapy*
Skin Neoplasms / immunology
Tumor Microenvironment / immunology

Substances

Antineoplastic Agents, Immunological
B7-H1 Antigen
Biomarkers, Tumor
CTLA-4 Antigen
CTLA4 protein, human