Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy

Xinyu Tang, Xinrui Mao, Peiwen Ling, Muxin Yu, Hua Pan, Jiaming Wang, Mingduo Liu, Hong Pan, Wen Qiu, Nan Che, Kai Zhang, Feifan Bao, Hongwei Peng, Qiang Ding, Shui Wang () and Wenbin Zhou ()
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Xinyu Tang: The First Affiliated Hospital with Nanjing Medical University
Xinrui Mao: The First Affiliated Hospital with Nanjing Medical University
Peiwen Ling: The First Affiliated Hospital with Nanjing Medical University
Muxin Yu: The First Affiliated Hospital with Nanjing Medical University
Hua Pan: Liyang Branch of Jiangsu Provincial People’s Hospital
Jiaming Wang: The First Affiliated Hospital with Nanjing Medical University
Mingduo Liu: The First Affiliated Hospital with Nanjing Medical University
Hong Pan: The First Affiliated Hospital with Nanjing Medical University
Wen Qiu: Nanjing Medical University
Nan Che: The First Affiliated Hospital with Nanjing Medical University
Kai Zhang: Nanjing Medical University
Feifan Bao: The First Clinical Medical College of Nanjing Medical University
Hongwei Peng: Liyang Branch of Jiangsu Provincial People’s Hospital
Qiang Ding: The First Affiliated Hospital with Nanjing Medical University
Shui Wang: The First Affiliated Hospital with Nanjing Medical University
Wenbin Zhou: The First Affiliated Hospital with Nanjing Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8+ T cells (TCM) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8+ T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8+ T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44hiCD62L+CD8+ TCM cells. Enhancement of CD8+ TCM cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8+ T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8+ T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8+ TCM cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.

Date: 2024
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DOI: 10.1038/s41467-024-49059-6

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