Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade

Andrea Gaißler, Trine Sundebo Meldgaard, Christina Heeke, Sepideh Babaei, Siri Amanda Tvingsholm, Jonas Bochem, Janine Spreuer, Teresa Amaral, Nikolaus Benjamin Wagner, Reinhild Klein, Friedegund Meier, Claus Garbe, Thomas K. Eigentler, Graham Pawelec, Manfred Claassen, Benjamin Weide, Sine Reker Hadrup, Kilian Wistuba-Hamprecht*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms.

Original languageEnglish
Article number906352
JournalFrontiers in Immunology
Volume13
Number of pages12
ISSN1664-3224
DOIs
Publication statusPublished - 2022

Keywords

  • Checkpoint blockade
  • Dextramer
  • Melanoma
  • Melanoma-associated antigen
  • Regression analysis
  • T cells

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