Intratumoral delivery of a highly active form of XCL1 enhances antitumor CTL responses through recruitment of CXCL9‐expressing conventional type‐1 dendritic cells

Abstract Conventional type 1 dendritic cells (cDC1s) play a crucial role in antitumor immunity through the induction and activation of tumor‐specific CD8 + cytotoxic T cells (CTLs). The chemokine XCL1 is a major chemotactic factor for cDC1s and its receptor XCR1 is selectively expressed on cDC1s. Here, we investigated the effect of intratumoral delivery of a highly active form of murine XCL1 (mXCL1‐V21C/A59C) on cDC1‐mediated antitumor immunity using a hydrophilic gel patch. The hydrophilic gel patch containing mXCL1‐V21C/A59C increased cDC1 accumulation in the tumor masses and promoted their migration to the regional lymph nodes, resulting in enhanced induction of tumor‐specific CTLs. Tumor‐infiltrating cDC1s not only expressed XCR1 but also produced CXCL9, a ligand for CXCR3 which is highly expressed on CTLs and NK cells. Consequently, CTLs and NK cells were increased in the tumor masses of mice treated with mXCL1‐V21C/A59C, while immunosuppressive cells such as monocyte‐derived suppressive cells and regulatory T cells were decreased. We also confirmed that anti‐CXCL9 treatment decreased the tumor infiltration of CTLs. The intratumoral delivery of mXCL1‐V21C/A59C significantly decreased tumor growth and prolonged survival in E.G7‐OVA and B16‐F10 tumor‐bearing mice. Furthermore, the antitumor effect of mXCL1‐V21CA59C was enhanced in combination with anti‐programmed cell death protein 1 treatment. Finally, using The Cancer Genome Atlas database, we found that XCL1 expression was positively correlated with tumor‐infiltrating cDC1s and a better prognosis in melanoma patients. Collectively, our findings provide a novel therapeutic approach to enhance tumor‐specific CTL responses through the selective recruitment of CXCL9‐expressing cDC1s into the tumor masses.