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CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity
Austin P. Huffman, … , Katelyn T. Byrne, Robert H. Vonderheide
Austin P. Huffman, … , Katelyn T. Byrne, Robert H. Vonderheide
Published April 23, 2020
Citation Information: JCI Insight. 2020;5(10):e137263. https://doi.org/10.1172/jci.insight.137263.
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Research Article Immunology Oncology

CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity

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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.

Authors

Austin P. Huffman, Jeffrey H. Lin, Samuel I. Kim, Katelyn T. Byrne, Robert H. Vonderheide

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Figure 1

Single-cell RNA-sequencing identifies intratumor immune populations.

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Single-cell RNA-sequencing identifies intratumor immune populations.
(A)...
(A) Treatment of mice subcutaneously implanted with clonal KPC cell line 4662.MD10 with combination CD40 agonist and anti–CTLA-4 with anti–PD-1 (ICB). CD45+ cells were sorted for single-cell transcriptomic analysis using the 10x Genomics platform 12 days after beginning therapy. (B) Tumor growth kinetics of subcutaneously implanted mice treated as shown in A. (C) UMAP nondimensional linear reduction and clustering of immune cell populations from the tumor microenvironment merged across all treatment conditions. (D) Scaled expression of cluster-specific genes visualized by heatmap. The mean expression of each gene across all clusters was scaled to 0 with a variance of 1. n = 4 mice per treatment group (A, C, and D). n = 10 mice per group (B). Error bars indicate mean ± SEM. *P < 0.05 (Student’s 2-tailed t test). Data shown in B are representative of 2 independent experiments with 5 to 10 mice per group. gMDSC, granulocytic myeloid-derived suppressor cell; mMDSC, monocytic myeloid-derived suppressor cell.
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