Higher proportions of CD39+ tumor-resident cytotoxic T cells predict recurrence-free survival in patients with stage III melanoma treated with adjuvant immunotherapy.

Autor:	Attrill GH; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Owen CN; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; The University of Bristol, Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK., Ahmed T; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia., Vergara IA; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Colebatch AJ; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia., Conway JW; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Nahar KJ; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Thompson JF; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital; Mater Hospital, Sydney, New South Wales, Australia., Pires da Silva I; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia., Carlino MS; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia., Menzies AM; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia., Lo S; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Palendira U; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Scolyer RA; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia., Long GV; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia., Wilmott JS; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia james.wilmott@sydney.edu.au.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jun; Vol. 10 (6).
DOI:	10.1136/jitc-2022-004771
Abstrakt:	Background: Adjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma. Methods: Associations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab/pembrolizumab±low-dose/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1. Results: With a median follow-up of 19.3 months, 37/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39-CD103-PD-1-CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1 year. Conclusions: Adjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer. Competing Interests: Competing interests: CNO reports non-financial support from Merck Sharp & Dohme. IPdS reports travel support by BMS and MSD, and speaker fees by Roche, BMS, MSD and Novartis. MSC reports personal fees from BMS, Merck Sharp & Dohme, Novartis, Roche, Amgen, Pierre-Fabre and Ideaya. JFT received honoraria for Advisory Board participation from Merck Sharpe & Dohme Australia and Bristol Myers Squibb Australia, honoraria and travel expenses from GlaxoSmithKline and Provectus, and conference attendance support from Novartis. AMM is on advisory boards for Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis Pharma AG, Roche, and Pierre‐Fabre and QBiotics. RAS received fees for professional services from Evaxion, Provectus Biopharmaceuticals Australia, QBiotics, Merck Sharp & Dohme, GlaxoSmithKline Australia, Bristol-Myers Squibb, Dermpedia, Novartis, Myriad, NeraCare and Amgen. GVL is consultant advisor for Aduro Biotech, Amgen, 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, Regeneron Pharmaceuticals, SkylineDX B.V. and Specialised Therapeutics Australia Pty Ltd. All remaining authors declared no competing interests. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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