Citation Information: JCI Insight. 2025;10(11):e177373. https://doi.org/10.1172/jci.insight.177373.
Abstract
While cytotoxic CD4+ tumor-infiltrating lymphocytes have anticancer activity in patients, whether these can be noninvasively monitored and how these are regulated remains obscure. By matching single cells with T cell receptors (TCRs) in tumor and blood of patients with bladder cancer, we identified distinct pools of tumor-matching cytotoxic CD4+ T cells in the periphery directly reflecting the predominant antigenic specificities of intratumoral CD4+ tumor-infiltrating lymphocytes. On one hand, the granzyme B–expressing (GZMB-expressing) cytotoxic CD4+ subset proliferated in blood in response to PD-1 blockade but was separately regulated by the killer cell lectin-like receptor G1 (KLRG1), which inhibited their killing by interacting with E-cadherin. Conversely, a clonally related, GZMK-expressing circulating CD4+ population demonstrated basal proliferation and a memory phenotype that may result from activation of GZMB+ cells, but was not directly mobilized by PD-1 blockade. As KLRG1 marked the majority of circulating tumor-TCR-matched cytotoxic CD4+ T cells, this work nominates KLRG1 as a means to isolate them from blood and provide a window into intratumoral CD4+ recognition, as well as a putative regulatory receptor to mobilize the cytolytic GZMB+ subset for therapeutic benefit. Our findings also underscore ontogenic relationships of GZMB- and GZMK-expressing populations and the distinct cues that regulate their activity.
Authors
Serena S. Kwek, Hai Yang, Tony Li, Arielle Ilano, Eric D. Chow, Li Zhang, Hewitt Chang, Diamond Luong, Averey Lea, Matthew Clark, Alec Starzinski, Yimin Shi, Elizabeth McCarthy, Sima Porten, Maxwell V. Meng, Chun Jimmie Ye, Lawrence Fong, David Y. Oh
