AUTHOR=Chu Xiao-Dong , Bao Hui , Lin Yu-Jian , Chen Ruo-Xi , Zhang Yi-Ran , Huang Ting , He Jia-Shuai , Huangfu Shu-Chen , Pan Yun-Long , Ding Hui 

TITLE=Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.965492

DOI=10.3389/fimmu.2022.965492

ISSN=1664-3224

ABSTRACT=Abstract
Introduction: The purpose of this study was to evaluate recombinant human endostatin (rHEs)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHEs and programmed death ligand-1(PD-L1) inhibitors. 
Methods: A mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intra-tumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+T cells in tumors was evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues.
Results: The antitumor effects of endostatin combined with PD-L1 inhibitor were significantly greater than those of endostatin or PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher D* and F values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of VEGF and TGF-β than the control group. Treatment of CD8+ T cells with endostatin for 24 hours did not alter the expression levels of markers of reduced T cell activity. However, endostatin reversed VEGF-mediated inhibition of secretion of IFN-γ from T cells. The results in colorectal cancer clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to infiltration density of CD8+T cells and overall survival time.
Conclusion: Endostatin improved the anti-tumor effects of PD-L1 inhibitors on colorectal cancer, significantly increased the activity of CD8+ T cells, and synergistically improve the tumor treatment effect of the two inhibitors.