The role of fibrocyte-like cells in combination treatment of immune checkpoint inhibitor with antiangiogenic agents

Background: Recent clinical trials indicate the combination treatment with immune checkpoint inhibitor and antiangiogenic drug improves the prognosis of lung cancer patients. However, its mechanism has been still unclear. We previously reported tumor tissue treated with anti-vascular endothelial growth factor (VEGF) antibody recruits the fibrocyte-like cells (FCs). We focus on the FCs as the key mediators of tumor immune microenvironment. Aims and Objectives: The purpose of this study is to investigate the roles of FCs in the combination therapy with anti-VEGF and anti-programmed death-ligand 1 (PD-L1) antibodies by using the subcutaneous mouse model of mesothelioma. Method: Mouse mesothelioma cell line (AB1-HA) bearing mice were treated with anti-VEGF and anti-PD-L1 antibodies. The number of tumor infiltrated immune cells was determined by immunohistochemistry. We confirmed the expression of immune checkpoint molecules and costimulatory molecules in mouse lung FCs by flowcytometry. To evaluate the roles of FCs on the effect of anti-PD-L1 antibody, we implanted the mouse lung FCs near the tumor tissue. Results: The combination therapy with low dose anti-VEGF and PD-L1 antibody suppressed the tumor progression more than monotherapy. We confirmed low dose anti-VEGF antibody increases the tumor infiltrated FCs. Mouse FCs expressed PD-L1, and costimulatory molecules CD86. The FCs implantation improved the therapeutic effect of anti-PD-L1 antibody, and increased the tumor infiltrated CD8+ T cells. Conclusions: The combination blockage of VEGF and PD-L1 has potential to improve the anti-tumor immunity via recruiting PD-L1+, CD86+ FCs and enhancing its antigen presentation.