Identification and regulation of circulating tumor-TCR-matched cytotoxic CD4+ lymphocytes by KLRG1 in bladder cancer
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
- Elizabeth A. McCarthy (ORCID: https://orcid.org/0000-0001-7321-9319)
- Chun Jimmie Ye (ORCID: https://orcid.org/0000-0001-6560-3783)
- Maxwell V. Meng (ORCID: https://orcid.org/0009-0007-8838-8212)
- Diamond Luong (ORCID: https://orcid.org/0000-0001-6832-5408)
- Yimin Shi (ORCID: https://orcid.org/0000-0002-9779-5967)
- Alec Starzinski (ORCID: https://orcid.org/0000-0001-5266-9660)
- Hewitt Chang (ORCID: https://orcid.org/0000-0001-9760-2304)
- Tony Li (ORCID: https://orcid.org/0000-0002-1234-1334)
- Arielle Ilano
- Hai Yang (ORCID: https://orcid.org/0000-0001-5210-8468)
- Sima P. Porten (ORCID: https://orcid.org/0000-0002-3948-4968)
- Matthew Clark (ORCID: https://orcid.org/0000-0003-0355-2516)
- Lawrence H. Fong (ORCID: https://orcid.org/0000-0002-6428-428X)
- Serena S. Kwek (ORCID: https://orcid.org/0000-0001-5097-2711)
- Eric D. Chow (ORCID: https://orcid.org/0000-0001-8079-918X)
- Li Zhang (ORCID: https://orcid.org/0000-0002-3617-2627)
- David Oh
- Averey Lea
Institutions
- University of California, San Francisco (US)
- Fred Hutch Cancer Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Institute of Human Genetics (PL)
- Chan Zuckerberg Initiative (United States) (US)
- Center for Rheumatology (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- U-M Rogel Cancer Center (US)
- University of San Francisco (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1172/jci.insight.177373
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Prostate Cancer Foundation
- Damon Runyon Cancer Research Foundation
- V Foundation for Cancer Research
- Amgen
- Bristol-Myers Squibb
- AstraZeneca
- Peter Michael Foundation
- Parker Institute for Cancer Immunotherapy
- Innovent Biologics
- Bavarian Nordic
- National Institutes of Health
- Genentech
- University of California, San Francisco
- Daiichi Sankyo Europe