Tumor-reactive LAG3+CD8+ T cells diverge into terminally exhausted cells and long-lived memory T cells.

Authors

Vaishali Aggarwal, Yangxi Sun, Chang Liu, Jian Cui, Sasikanth Manne, Yingtong Dou, Qiang Chen, Erin A Brunazzi, Kate M Vignali, Haiguang Wang, E John Wherry, Creg J Workman, Dario A A Vignali

Published in

The Journal of experimental medicine. Volume 223. Issue 9. Sep 07, 2026. Epub Aug 18, 2026.

Abstract

Chronic T cell stimulation in tumors and chronic viral infections leads to T cell exhaustion, a state of dysfunction. As LAG3 marks a prominent subset of exhausted T (TEX) cells in mid-to-late stage tumors, we generated a Lag3 lineage-tracing mouse model (Lag3iCreERT2Rosa26LSL-tdTomato) to fate map and characterize tumor-reactive LAG3+CD8+ TEX cells. In tumor-bearing mice, two distinct tumor-specific tdTomato+ CD8+ T cell subsets stratified by LAG3 surface expression (LAG3+tdT+ and LAG3-tdT+) exhibited contrasting anatomical distributions, functionality and transcriptional profiles, yet shared TCR clonotypes, suggesting a common origin. While LAG3+tdT+ CD8+ TEX cells were restricted to the tumor microenvironment and predominantly terminally exhausted, LAG3-tdT+ CD8+ TEX cells were progenitors that persisted in vivo and are required for anti-tumor immunity against a secondary tumor challenge. This study highlights TEX cell functional heterogeneity and plasticity and characterizes a unique fate-flexible LAG3-tdT+ progenitor TEX subset that drives an anti-tumor memory response, supporting antibody-based therapeutic targeting of LAG3+ TEX cells to unleash anti-tumor immunity and promote durability.

PMID:
42611047
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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