To investigate the mechanism of agonist (ag) CD40-driven intratumoral CD4+ T cell chemotaxis, Huffman and Lin et al. evaluated the effects of checkpoint blockade (ICB) with or without agCD40 in a SQ model of pancreatic cancer, requiring both CD4+ and CD8+ T cells for tumor regression. 10X Genomics scRNA sequencing revealed that agCD40/ICB broadly increased chemokine CCL5 expression by intratumoral myeloid cells, compared to ICB alone, and tumor regression was abrogated by CCL5 knockout or anti-CCL5 treatment. CCL5 recruitment was selective for CD4+ T cells, highlighting a role in CD4+ T cell-mediated tumor chemotaxis.

Contributed by Katherine Turner

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.

Author Info: (1) Perelman School of Medicine, University of Pennsylvanis, Philadelphia, United States of America. (2) Perelman School of Medicine, University of Pennsylvania, Philadelphia, Unit

Author Info: (1) Perelman School of Medicine, University of Pennsylvanis, Philadelphia, United States of America. (2) Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (3) Perelman School of Medicine, University of Pennsylvanis, Philadelphia, United States of America. (4) Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (5) Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.