Inhibition of APOE potentiates immune checkpoint therapy for cancer

Int J Biol Sci. 2022 Aug 15;18(14):5230-5240. doi: 10.7150/ijbs.70117. eCollection 2022.


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 αPD-1 (anti-PD-1) immunotherapy. Moreover, treatment by exploiting APOE inhibitor (COG 133TFA, αAPOE) was capable of curbing tumor development and fostering regression if in combination of αPD-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 αPD-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.

Keywords: APOE; PD-1; TIGIT; macrophage; single-cell RNA sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E* / antagonists & inhibitors
  • Apoproteins*
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Ligands
  • Lipoproteins, LDL
  • Mice
  • Mice, Knockout, ApoE
  • Neoplasms* / drug therapy
  • Tumor Microenvironment


  • Apolipoproteins E
  • Apoproteins
  • Immune Checkpoint Inhibitors
  • Ligands
  • Lipoproteins, LDL