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Brief Report

Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma

1
Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
2
Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
3
Department of Medical Oncology, Chris O’Brien Lifehouse, Sydney, NSW 2050, Australia
4
Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
5
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, NSW 2050, Australia
6
Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
7
Department of Neurosurgery, Chris O’Brien Lifehouse, Sydney, NSW 2050, Australia
8
Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
9
Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW 2145, Australia
10
Department of Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
11
Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW 2065, Australia
12
Department of Medical Oncology, Mater Hospital, Sydney, NSW 2060, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(11), 3374; https://doi.org/10.3390/cancers12113374
Received: 9 October 2020 / Revised: 10 November 2020 / Accepted: 11 November 2020 / Published: 14 November 2020
(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)
Immunotherapy leads to durable responses in a proportion of patients with advanced melanoma. Combination immunotherapy is more efficacious than single-agent immunotherapy, yet it is associated with significant toxicity. Currently there are no robust biomarkers to guide first-line immunotherapy selection. We have developed a flow cytometry-based score, to quantify the expression of antigen-presenting molecules MHC-I and MHC-II on melanoma cells, that incorporates both the fraction of tumor cells expressing MHC molecules and the level of expression. We demonstrate that the evaluation of tumor cell surface MHC-I expression aids in treatment selection, with combination immunotherapy providing clinical benefit over single-agent immunotherapy in MHC-I low melanoma with poor immune cell infiltration.
Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma. View Full-Text
Keywords: immune checkpoint blockade; anti-PD-1; combination immunotherapy; major histocompatibility (MHC) class I; metastatic melanoma immune checkpoint blockade; anti-PD-1; combination immunotherapy; major histocompatibility (MHC) class I; metastatic melanoma
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Figure 1

MDPI and ACS Style

Shklovskaya, E.; Lee, J.H.; Lim, S.Y.; Stewart, A.; Pedersen, B.; Ferguson, P.; Saw, R.P.; Thompson, J.F.; Shivalingam, B.; Carlino, M.S.; Scolyer, R.A.; Menzies, A.M.; Long, G.V.; Kefford, R.F.; Rizos, H. Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma. Cancers 2020, 12, 3374. https://doi.org/10.3390/cancers12113374

AMA Style

Shklovskaya E, Lee JH, Lim SY, Stewart A, Pedersen B, Ferguson P, Saw RP, Thompson JF, Shivalingam B, Carlino MS, Scolyer RA, Menzies AM, Long GV, Kefford RF, Rizos H. Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma. Cancers. 2020; 12(11):3374. https://doi.org/10.3390/cancers12113374

Chicago/Turabian Style

Shklovskaya, Elena, Jenny H. Lee, Su Y. Lim, Ashleigh Stewart, Bernadette Pedersen, Peter Ferguson, Robyn P. Saw, John F. Thompson, Brindha Shivalingam, Matteo S. Carlino, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long, Richard F. Kefford, and Helen Rizos. 2020. "Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma" Cancers 12, no. 11: 3374. https://doi.org/10.3390/cancers12113374

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