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

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Qiaoying Lv, Tong Su, Wei Liu, Lulu Wang, Jiali Hu, Yali Cheng, Chengcheng Ning, Weiwei Shan, Xuezhen Luo, Xiaojun Chen
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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.

低血清载脂蛋白 A1 通过 HIF-1α 糖酵解途径损害 CD8+ T 细胞的抗肿瘤免疫力
免疫抑制微环境会促进肿瘤的发生和发展。低载脂蛋白 A1(ApoA1)与肿瘤发生密切相关,但其潜在机制尚不清楚。本研究调查了子宫内膜癌、卵巢癌和肺癌患者血清载脂蛋白A1水平与免疫微环境之间的关系。与健康对照组相比,子宫内膜癌和卵巢癌患者的血清载脂蛋白A1水平明显下降。在子宫内膜癌组织中,与血清载脂蛋白A1正常组相比,低血清载脂蛋白A1组的CD163+巨噬细胞浸润增加,CD8+T细胞浸润减少。肿瘤携带载脂蛋白A1基因敲除小鼠的肿瘤浸润CD8+ T细胞功能受损,CD8+ T细胞浸润减少。CD8+ T细胞耗竭实验证实,载脂蛋白A1以CD8+ T细胞依赖的方式发挥抗肿瘤活性。体外实验表明,载脂蛋白A1模拟肽L-4F通过HIF-1α介导的糖酵解途径直接增强了CD8+ T细胞的抗肿瘤活性。从机理上讲,载脂蛋白A1通过下调HIF-1α亚基α抑制剂来抑制泛素介导的HIF-1α蛋白降解。这一调控过程维持了 HIF-1α 蛋白的稳定性,并激活了 HIF-1α 信号通路。肿瘤携带载脂蛋白A1的转基因小鼠对抗PD-1疗法的反应增强,导致肿瘤生长减少、活化的CD8+ T细胞浸润增加以及肿瘤坏死增强。本文报告的数据证明了载脂蛋白A1在通过HIF-1α介导的糖酵解增强CD8+ T细胞免疫功能方面的关键作用,并支持将补充载脂蛋白A1与抗PD-1疗法相结合治疗癌症的临床研究。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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