TY - JOUR
T1 - Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade
AU - Gaißler, Andrea
AU - Meldgaard, Trine Sundebo
AU - Heeke, Christina
AU - Babaei, Sepideh
AU - Tvingsholm, Siri Amanda
AU - Bochem, Jonas
AU - Spreuer, Janine
AU - Amaral, Teresa
AU - Wagner, Nikolaus Benjamin
AU - Klein, Reinhild
AU - Meier, Friedegund
AU - Garbe, Claus
AU - Eigentler, Thomas K.
AU - Pawelec, Graham
AU - Claassen, Manfred
AU - Weide, Benjamin
AU - Hadrup, Sine Reker
AU - Wistuba-Hamprecht, Kilian
N1 - Publisher Copyright:
Copyright © 2022 Gaißler, Meldgaard, Heeke, Babaei, Tvingsholm, Bochem, Spreuer, Amaral, Wagner, Klein, Meier, Garbe, Eigentler, Pawelec, Claassen, Weide, Hadrup and Wistuba-Hamprecht.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Checkpoint blockade
KW - Dextramer
KW - Melanoma
KW - Melanoma-associated antigen
KW - Regression analysis
KW - T cells
U2 - 10.3389/fimmu.2022.906352
DO - 10.3389/fimmu.2022.906352
M3 - Journal article
C2 - 35874702
AN - SCOPUS:85134476287
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 906352
ER -