Abstract C172: PTX3 blockade restores anti-tumor immunity through suppressing M2-like macrophages phenotypes in colon cancer

Abstract

Abstract The tumor microenvironment is a chronic inflammatory condition which is composed of various types of stromal cells, immune cells, and cytokines. Cancer-associated fibroblasts and M2-like macrophages are involved in enhancing malignancy of colon cancer progression, such as tumor growth and immunosuppression. Identifying the cross-talk mechanisms among cancer cells, cancer-associated fibroblasts, and M2-like macrophages is important for development of cancer therapy. Pentraxin 3 (PTX3) is a secretory factor that is rapidly responsive to exposure of proinflammatory cytokines. The function of PTX3 is known to regulate innate immunity and tissue remodeling. However, its role in tumor progression appears to be context-dependent and unclear. In this study, we found that PTX3 is silenced in colon cancer cells due to epigenetic regulation but is primarily expressed by fibroblasts in colon tumors. Clinically, higher PTX3 expression is positively correlated with fibroblast and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Our results showed that PTX3 had no effect on cellular proliferation of fibroblasts or cancer cells in vitro, but blockade of PTX3 by specific monoclonal antibody significantly reduced stroma cell-mediated tumor growth in vivo. In addition, blockade of PTX3 reduced MC38 tumor growth in immunocompetent mice but had no effect in immunodeficient mice, suggesting the role of PTX3 in regulating tumor-immunity. Indeed, inhibition of PTX3 resulted in reduced numbers of M2-like macrophages and increased numbers of cytotoxic CD8 T cells in MC38 tumors. The expressions of cytotoxic markers in T cells were suppressed under exposure to conditioned media from PTX3-stimulated macrophages in vitro. We further revealed that PTX3 stimulated macrophage polarization toward an M2-like phenotype through activation of CREB/CEBPB axis. These findings suggest that PTX3 is involved in stroma cell-mediated protumoral immunity and targeting PTX3 by monoclonal antibody can be a potential therapeutic strategy in colon cancer treatment. Citation Format: Feng-Wei Chen. PTX3 blockade restores anti-tumor immunity through suppressing M2-like macrophages phenotypes in colon cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C172.