C-Type Lectin Receptors CLEC4A and CLEC12A on Peripheral Myeloid Cells Are Inversely Associated with Cancer Patients Prognosis

Introduction: C-type lectins are immunoregulatory receptors implicated in tumor progression, poor prognosis, and immune suppression. We recently identified a cluster of C-type lectins associated with survival in glioblastoma patients. However, their role in cancer remains poorly understood. Aim: To investigate the expression of C-type lectins on myeloid cells and evaluate their potential as immune biomarkers in cancer patients. Methods: Single-cell RNA sequencing data from the TISCH2 database were analyzed to assess the distribution of C-type lectins across immune cell subsets in different solid tumors. The expression of CLEC4A and CLEC12A on circulating myeloid cells (CD45+ cells, monocytes, LOX1+ PMN-MDSCs, and M-MDSCs) was evaluated by multiparametric flow cytometry in peripheral blood samples from 70 cancer patients with various solid tumors and 6 healthy donors. Statistical comparisons were performed using the unpaired Student’s t-test. Overall survival was analyzed using the Kaplan–Meier method and log-rank test. Results: scRNA-seq analysis on TISCH2 revealed that both C-type lectins are expressed in all cancer histotype analyzed in association with myeloid cells, particularly monocytes and macrophages. C-type lectins were analyzed by flow-cytometry to validate bioinformatic analysis on PBMCs of HD and cancer patients. CLEC4A and CLEC12A were significantly upregulated in cancer patients on circulating immune cells, particularly on M-MDSCs, compared to HD. To evaluate the prognostic significance of C-type lectins, cancer patients were divided into two groups based on the median expression of CLEC4A and CLEC12A on the different myeloid subsets. Kaplan-Meier survival analysis revealed that high expression levels of CLEC4A and CLEC12A on circulating immune cells (both total CD45+ and M-MDSCs) were significantly associated with poor overall-survival. Interestingly, total CD45+ cells and M-MDSC did not show a correlation with prognosis. Conclusions: CLEC4A+ and CLEC12A+ M-MDSC may be exploited as potential circulating biomarkers of prognosis in cancer patients.