CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity.
JCI Insight
; 5(10)2020 05 21.
Article
en En
| MEDLINE
| ID: mdl-32324594
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 intratumor 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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Linfocitos T CD4-Positivos
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Linfocitos Infiltrantes de Tumor
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Quimiocina CCL5
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Antígenos CD40
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Neoplasias Experimentales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
JCI Insight
Año:
2020
Tipo del documento:
Article