Uto et al. showed that when the homotypic C-type lectin receptor Clec4A4, found on certain cDC subsets, was knocked out in mice, the mice exhibited reduced tumor progression and enhanced antigen-specific priming of adoptively-transferred T cells in TdLNs. The TMEs of Clec4A4 KO mice had more activated cDCs and TILs, fewer MDSCs, and lower expression of suppressive soluble factors than the TMEs of WT mice. Treating human CLEC4A-Tg mice with a blocking anti-human CLEC4A mAb inhibited progression of established tumors and Treg cell accumulation in tumor tissues, boosted antitumor responses without inducing adverse events, and had additive effects when combined with anti-PD-1.
Contributed by Paula Hochman
ABSTRACT: Clec4A4 is a C-type lectin receptor (CLR) exclusively expressed on murine conventional dendritic cells (cDCs) to regulate their activation status. However, the functional role of murine Clec4A4 (mClec4A4) in antitumor immunity remains unclear. Here, we show that mClec4A4 serves as a negative immune checkpoint regulator to impair antitumor immune responses. Deficiency of mClec4A4 lead to a reduction in tumor development, accompanied by enhanced antitumor immune responses and amelioration of the immunosuppressive tumor microenvironment mediated through the enforced activation of cDCs in tumor-bearing mice. Furthermore, antagonistic monoclonal antibody (mAb) to human CLEC4A (hCLEC4A), which is the functional orthologue of mClec4A4, exerted protection against established tumors without any apparent signs of immune-related adverse events in hCLEC4A-transgenic mice. Thus, our findings highlight the critical role of mClec4A4 expressed on cDCs as a negative immune checkpoint molecule in the control of tumor progression and provide support for hCLEC4A as a potential target for immune checkpoint blockade in tumor immunotherapy.
Author Info: (1) Faculty of Medicine, University of Miyazaki, Miyazaki, Miyazaki, Japan. (2) Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. (3) University of Miyazaki, Miyazaki,
Author Info: (1) Faculty of Medicine, University of Miyazaki, Miyazaki, Miyazaki, Japan. (2) Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. (3) University of Miyazaki, Miyazaki, Japan. (4) Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. (5) University of Miyazaki, Miyazaki, Japan. (6) Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. (7) Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. (8) University of Miyazaki, Miyazaki, Japan.
