Inhibition of APOE potentiates immune checkpoint therapy for cancer
Bingqing Hui, Lü Chen, Haiyang Li, Xiaopei Hao, Hanyuan Liu, Danping Zhuo, Qian Wang, Zhouxiao Li, Li Liu, Xuehao Wang, Yanhong Gu, Weiwei Tang
Abstract
Checkpoint immunotherapy is capable of unleashing T cells for controlling tumor, whereas it is destroyed by immunosuppressive myeloid cell. Apoprotein E (APOE) refers to a ligand in terms of the members of low-density lipoprotein (LDL) receptor family for mediating Apoprotein B-involving atherogenic lipoprotein clearance. Besides, tumor-infiltration macrophage can express APOE. The present study reported Apoe -/-mice to exhibit higher resistance toward the development of three types of carcinomas as compared with mice with wild type and to have greater responses to PD-1 (anti-PD-1) immunotherapy. Moreover, treatment by exploiting APOE inhibitor (COG 133TFA, APOE) was capable of curbing tumor development and fostering regression if in combination of PD-1. According to single-cell RNA sequencing (scRNA-seq), Apoe deletion was correlated with the decline of C1QC + and CCR2 + macrophage within tumor infiltration, and mass spectrometry results noticeably showed down-regulated the number of M2 macrophages as well. Furthermore, APOE expression in cancer patients resistant to PD-1 treatment significantly exceeded that in the sensitive group. For this reason, APOE is likely to be targeted for modifying tumor macrophage infiltrate and augmenting checkpoint immunotherapy.