CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity
Open Access
- 21 May 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 5 (10)
- https://doi.org/10.1172/jci.insight.137263
Abstract
The role CD4+ T-cells play in tumor immunity is less well-appreciated than the cytotoxic role of CD8+ T-cells. Despite clear evidence for CD4+ T-cell dependency across multiple immunotherapies, the mechanisms by which CD4+ T-cells infiltrate tumors remain poorly understood. Prior studies by our group have shown in a mouse model of pancreatic cancer that systemic activation of the cell-surface TNF superfamily member CD40 drives T-cell infiltration into tumors and in combination with immune checkpoint blockade, leads to durable tumor regressions and cures that depend on both CD8+ and CD4+ T-cells. Here, we used single-cell transcriptomics to examine the tumor microenvironment following treatment with agonist CD40 antibody with or without immune checkpoint blockade. We show that intratumoral myeloid cells produce the chemokine CCL5 in response to CD40 agonist and that CCL5 mediates an influx of CD4+ T-cells into the tumor microenvironment. Disruption of CCL5 genetically or pharmacologically mitigates the influx of CD4+ but not CD8+ T-cells into tumors and blunts the therapeutic efficacy of immunotherapy. These findings highlight a previously unappreciated role for CCL5 in selectively mediating CD4+ T-cell tumor infiltration in response to effective immunotherapy.Keywords
Funding Information
- National Cancer Institute (R01 CA229803)
- National Cancer Institute (P30 CA016520)
- National Cancer Institute (P01 CA210944)
- Parker Institute for Cancer Immunotherapy (NA)
This publication has 55 references indexed in Scilit:
- Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host DiseaseThe New England Journal of Medicine, 2012
- CCL5 Neutralization Restricts Cancer Growth and Potentiates the Targeting of PDGFRβ in Colorectal CarcinomaPLOS ONE, 2011
- A Role for the Chemokine RANTES in Regulating CD8 T Cell Responses during Chronic Viral InfectionPLoS Pathogens, 2011
- CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and HumansScience, 2011
- Dual Control of Antitumor CD8 T Cells through the Programmed Death-1/Programmed Death-Ligand 1 Pathway and Immunosuppressive CD4 T Cells: Regulation and CounterregulationThe Journal of Immunology, 2009
- Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell RecruitmentCancer Research, 2009
- Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal AntibodyJournal of Clinical Oncology, 2007
- Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in miceCancer Cell, 2005
- Impaired T Cell Function in RANTES-Deficient MiceClinical Immunology, 2002
- The CD40 Antigen and its LigandAnnual Review of Immunology, 1994