Low Serum Apolipoprotein A1 Levels Impair Antitumor Immunity of CD8+ T Cells via the HIF-1α–Glycolysis Pathway

糖酵解 免疫 CD8型 细胞毒性T细胞 免疫疗法 免疫学 癌症研究 医学 生物 免疫系统 内科学 载脂蛋白B 生物化学 新陈代谢 体外 胆固醇
作者
Qiaoying Lv,Tong Su,Wei Liu,Lulu Wang,Jiali Hu,Yali Cheng,Chengcheng Ning,Weiwei Shan,Xuezhen Luo,Xiaojun Chen
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:12 (8): 1058-1073 被引量:2
标识
DOI:10.1158/2326-6066.cir-23-0506
摘要

Abstract An immunosuppressive microenvironment promotes the occurrence and development of tumors. Low apolipoprotein A1 (ApoA1) is closely related to tumor development, but the underlying mechanisms are unclear. This study investigated the association between serum ApoA1 levels and the immune microenvironment in endometrial, ovarian, and lung cancers. The serum ApoA1 level was decreased significantly in patients with endometrial and ovarian cancers compared with healthy controls. In endometrial cancer (EC) tissues, the low serum ApoA1 level group showed increased CD163+ macrophage infiltration and decreased CD8+ T-cell infiltration compared with the normal serum ApoA1 group. Compromised tumor-infiltrating CD8+ T-cell functions and decreased CD8+ T-cell infiltration also were found in tumor-bearing Apo1-knockout mice. CD8+ T-cell depletion experiments confirmed that ApoA1 exerted its antitumor activity in a CD8+ T-cell–dependent manner. In vitro experiments showed that the ApoA1 mimetic peptide L-4F directly potentiated the antitumor activity of CD8+ T cells via a HIF-1α–mediated glycolysis pathway. Mechanistically, ApoA1 suppressed ubiquitin-mediated degradation of HIF-1α protein by downregulating HIF-1α subunit α inhibitor. This regulatory process maintained the stability of HIF-1α protein and activated the HIF-1α signaling pathway. Tumor-bearing Apoa1 transgenic mice showed an increased response to anti–PD-1 therapy, leading to reduced tumor growth along with increased infiltration of activated CD8+ T cells and enhanced tumor necrosis. The data reported herein demonstrate critical roles for ApoA1 in enhancing CD8+ T-cell immune functions via HIF-1α–mediated glycolysis and support clinical investigation of combining ApoA1 supplementation with anti–PD-1 therapy for treating cancer.
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