Targeting Olfml3 In Colorectal Cancer Suppresses Tumor Growth And Angiogenesis, And Increases The Efficacy Of Anti-Pd1 Based Immunotherapy

Simple Summary Tumor vascularization promotes tumor growth and is intimately connected to immune system function. Despite efforts to use antiangiogenic therapies, their clinical effects are less pronounced than expected. Compensatory angiogenic responses and resistance to treatment are responsible for these limited therapeutic effects. Inhibition of OLFML3 suppresses the growth of colorectal cancer in preclinical models. Our study identified OLFML3 as a key regulator of angiogenesis, lymphangiogenesis, pericyte coverage, tumor-associated macrophage recruitment, and enhanced NKT lymphocyte recruitment associated with its antitumor effects. We also highlight that OLFML3 antibodies increase the efficacy of anti-PD-1-based therapies. These results are in agreement with the high expression of OLFML3 observed in colorectal carcinoma patients associated with shorter relapse-free survival, higher grade, and angiogenic microsatellite stable (CMS4) subtype. Clinically, high OLFML3 expression correlates with reduced disease-free survival in human colorectal cancer patients, suggesting a potential role as a therapeutic target. The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC.