OC 75.5 - Immune modulation by the endothelial protein C receptor (EPCR) in cancer progression

Background: The coagulation system is part of the innate immune defense. In malignancy, coagulation proteases and their receptors, especially the endothelial protein C receptor (EPCR) contribute to immune evasion and tumor progression. EPCR is expressed by tumor-associated macrophages (TAMs) and dendritic cells (DCs) and forms complexes with activated protein C, FVIIa and FXa that cleave protease-activated receptors (PARs) thereby modulating immune cell phenotypes. We recently demonstrated that macrophage-derived FXa as part of the EPCR-TF-FVIIa-FXa signaling complex cleaves PAR2 promoting tumor growth.

Aims: We aimed to delineate the functional contributions of EPCR expressed by TAMs and DCs to primary tumor progression.

Methods: We evaluated tumor growth in the spontaneous breast cancer model PyMT and the transplantable tumor model T241 in immunocompetent mice with cell-type specific deletions of EPCR in TAMs (EPCRfloxLysM-cre) or in DCs (EPCRfloxCD11c-cre) with or without concomitant anti-PD-L1 treatment. We characterized macrophages and DCs in the tumor microenvironments and tumor-draining lymph nodes (dLN) by multicolor-flow cytometry and mRNA-expression profiling.

Results: EPCR deletion in TAMs attenuated tumor growth and reduced the abundance of immunosuppressive TAMs in both tumor models. CD103+ DCs were slightly expanded in the TME, but similar in dLN of PyMT-EPCRfloxLysM-cre and control mice. However, progenitor and terminally exhausted T cells were reduced in myeloid cell EPCR-deficient mice. In contrast, EPCR deletion in DCs led to lower abundance of CD103+ DCs and faster tumor growth that could not be rescued by anti-PD-L1 treatment. In addition, DCs produced less IL-12 in the dLN of PyMT-EPCRfloxCD11c-cre mice. Consistently, in vitro generated DCs from EPCR- or EPCR recycling-deficient mice also showed reduced IL12 production and reduced antigen uptake.

Conclusion(s): Thus, EPCR has immune cell type-specific roles in tumor progression. EPCR+ TAMs mediate immunosuppression in the TME favoring tumor growth, whereas EPCR on DCs regulates IL12 production and antitumor immunity.