Quinic Acid Inhibits the Function of Myeloid-Derived Suppressor Cells to Enhance the Efficacy of Anti-PD1 against Colon Cancer

• Published in: Pharmaceutical research Vol. 35; no. 9
• Main Authors: Lin, HongYue, Wu, YuZhu, Chen, JinPing, Huang, ShuRong, Wang, YangQiang
• Format: Journal Article
• Language: English
• Published: Springer 01-09-2018
• Subjects: Analysis; Apoptosis; Colon cancer; Gastrointestinal diseases; Immunotherapy; T cells; Tumors
• ISSN: 0724-8741
• DOI: 10.1007/s11095-018-2459-5

Purpose Immunotherapy in the clinic has demonstrated its potential to control cancer through disinhibiting the immune system, especially for immune checkpoint inhibitors such as anti-programmed cell death protein 1/anti-programmed death-ligand 1 (anti-PD1/anti-PD-L1). However, although these new immunotherapies have resulted in durable clinical responses in various cancers, multiple mechanisms of immune resistance and suppression exist in tumors. One significant barrier to efficacy of anti-PD1 against colon cancer may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Here we demonstrated functional inhibition of G-MDSC with (-)-4-O-(4-O-[beta]-D-glucopyranosylcaffeoyl) quinic acid (QA), an inhibitor of PI3K[delta]/[gamma], reshaped the tumor immune microenvironment and promoted cytotoxic T cell-mediated tumor regression, resultantly enhancing responses to anti-PD1 treatment in colon tumor model. Methods A syngeneic colon tumor mouse model was used to study the effects of QA on tumor immune microenvironment and its potential synergistic effects with anti-PD1 blockade. Results QA treatment inhibited G-MDSC function in the tumor tissue. Additionally, combination treatment induced CD8+ T lymphocyte-dependent tumor growth delay and prolonged survival time in colon cancer. Conclusions Our results offered opportunities for new combination strategies using a selective small molecule PI3K[delta]/[gamma] inhibitor, to suppress MDSCs to enhance responses to immune checkpoint blockade in colon cancer.