Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets

Tuba N. Gide; Inês Pires da Silva; Camelia Quek; Peter M. Ferguson; Marcel Batten; Ping Shang; Tasnia Ahmed; Alexander M. Menzies; Matteo S. Carlino; Robyn P. M. Saw; John F. Thompson; Richard A. Scolyer; Georgina V. Long; James S. Wilmott

doi:10.3390/cancers13133186

Cancers (Jun 2021)

Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets

Tuba N. Gide,
Inês Pires da Silva,
Camelia Quek,
Peter M. Ferguson,
Marcel Batten,
Ping Shang,
Tasnia Ahmed,
Alexander M. Menzies,
Matteo S. Carlino,
Robyn P. M. Saw,
John F. Thompson,
Richard A. Scolyer,
Georgina V. Long,
James S. Wilmott

Affiliations

Tuba N. Gide: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Inês Pires da Silva: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Camelia Quek: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Peter M. Ferguson: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Marcel Batten: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Ping Shang: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Tasnia Ahmed: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Alexander M. Menzies: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Matteo S. Carlino: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Robyn P. M. Saw: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
John F. Thompson: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Richard A. Scolyer: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
Georgina V. Long: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
James S. Wilmott: Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia

DOI: https://doi.org/10.3390/cancers13133186
Journal volume & issue: Vol. 13, no. 13
p. 3186

Abstract

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While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/− anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group (n = 17) expressing genes associated with immune and T cell signalling, and a second group (n = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also subdivided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs (p = 0.04) and CD68+ macrophages (p = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors (p = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how individual treatment strategies can be achieved.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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