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

doi:10.1016/j.ccell.2021.11.012

. 2022 Jan 10;40(1):88-102.e7.

doi: 10.1016/j.ccell.2021.11.012. Epub 2021 Dec 23.

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

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

Free article

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

Felicity Newell et al. Cancer Cell. 2022.

Free article

. 2022 Jan 10;40(1):88-102.e7.

doi: 10.1016/j.ccell.2021.11.012. Epub 2021 Dec 23.

Authors

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests I.P.S. has received travel support by BMS and MSD, and speaker fee by Roche, BMS, MSD, and Novartis. J.F.T. has received honoraria for advisory board participation from Merck Sharpe Dohme Australia and Bristol Myers Squibb Australia and received honoraria and travel expenses from GSK and Provectus Inc. R.A.S. has received fees for professional services from Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics Group Limited, Novartis Pharma AG, MSD Sharp & Dohme (Australia), NeraCare, AMGEN Inc., Bristol-Myers Squibb, Novartis Pharmaceuticals Australia Pty Limited, Myriad Genetics GmbH, and GlaxoSmithKline Australia. G.V.L. is consultant advisor for Aduro Biotech Inc, Agenus Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. R.P.M.S has participated in advisory boards for MSD, Novartis, and Qbiotics and received speaking honoraria from BMS. J.V.P. and N.W. are founders and shareholders of genomiQa Pty Ltd, and members of its Board. M.S.C. is a consultant advisor to MSD, BMS, Novartis, Roche, Pierre Fabre, Sanofi, Merck Serono, Nektar, Eisia, and Ideaya and received honoraria from MSD, BMS, and Novartis. A.M.M. has participated in advisory boards for BMS, MSD, Novartis, Roche, and Pierre-Fabre. C.U.B. has served on advisory boards for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; received research funding from BMS, MSD, 4SC, Novartis, and NanoString; has stock ownership in Uniti Cars; and is a cofounder of Immagene BV. The remaining authors declare no competing interests.

Comment in

Multi-omics prediction in melanoma immunotherapy: A new brick in the wall.
Robert C, Gautheret D. Robert C, et al. Cancer Cell. 2022 Jan 10;40(1):14-16. doi: 10.1016/j.ccell.2021.12.008. Cancer Cell. 2022. PMID: 35016026

Cited by

The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.
Dravillas CE, Coleman SS 4th, Hoyd R, Caryotakis G, Denko L, Chan CHF, Churchman ML, Denko N, Dodd RD, Eljilany I, Hardikar S, Husain M, Ikeguchi AP, Jin N, Ma Q, McCarter MD, Osman AEG, Robinson LA, Singer EA, Tinoco G, Ulrich CM, Zakharia Y, Spakowicz D, Tarhini AA, Tan AC; exORIEN Consortium. Dravillas CE, et al. Cancer Res Commun. 2024 Aug 1;4(8):1978-1990. doi: 10.1158/2767-9764.CRC-23-0170. Cancer Res Commun. 2024. PMID: 39015091 Free PMC article.
Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma-A Real World Single-Center Analysis.
Hoffmann M, Hayoz S, Özdemir BC. Hoffmann M, et al. Biology (Basel). 2022 Mar 10;11(3):422. doi: 10.3390/biology11030422. Biology (Basel). 2022. PMID: 35336796 Free PMC article.
Molecular Classifiers in Skin Cancers: Challenges and Promises.
Azimi A, Fernandez-Peñas P. Azimi A, et al. Cancers (Basel). 2023 Sep 7;15(18):4463. doi: 10.3390/cancers15184463. Cancers (Basel). 2023. PMID: 37760432 Free PMC article. Review.
Creating a multifaceted prognostic model for cutaneous melanoma: the convergence of single-cell and bulk sequencing with machine learning.
Mao F, Wan N. Mao F, et al. Front Cell Dev Biol. 2024 May 6;12:1401945. doi: 10.3389/fcell.2024.1401945. eCollection 2024. Front Cell Dev Biol. 2024. PMID: 38770150 Free PMC article.
Challenges and the Evolving Landscape of Assessing Blood-Based PD-L1 Expression as a Biomarker for Anti-PD-(L)1 Immunotherapy.
Wang T, Denman D, Bacot SM, Feldman GM. Wang T, et al. Biomedicines. 2022 May 20;10(5):1181. doi: 10.3390/biomedicines10051181. Biomedicines. 2022. PMID: 35625917 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- H1 Connect
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases