EP010/#59  Insufficient serum apolipoprotein A1 impairs antitumor response of CD8+ T cell via HIF-1Α-glycolysis pathway

• Published in: International journal of gynecological cancer Vol. 33; no. Suppl 4; p. A88
• Main Authors: Lv, Qiaoying, Chen, Xiaojun
• Format: Journal Article
• Language: English
• Published: Oxford BMJ Publishing Group Ltd 07.11.2023; BMJ Publishing Group LTD
• Subjects: Endometrial cancer; ePoster Viewing; Lymphocytes; Ovarian cancer; Tumors
• ISSN: 1048-891X; 1525-1438
• DOI: 10.1136/ijgc-2023-IGCS.141

IntroductionThe immunosuppressive microenvironment plays an important role in the occurrence and development of tumors. Studies have shown that ApoA1 insufficiency is closely related to tumor development, but the underlying mechanisms are not well understood.MethodsSerum lipids in endometrial cancer and ovarian cancer patients were compared. Then tumor models in ApoA1 transgenic mice, and in vitro experiments were used to identify the immunomodulatory roles and potential mechanisms of ApoA1 on CD8+ T cells.ResultsSerum ApoA1 significantly decreased among the lipid parameters in patients with endometrial cancer and ovarian cancer compared to healthy controls. In endometrial cancer tissues, compared to ApoA1 sufficiency group, ApoA1 insufficiency group showed an immunosuppressive state, manifested as increased CD163+ macrophages and decreased CD8+ T cell infiltration. Consistently, tumor-bearing A1KO mice also showed impared tumor-infiltrating CD8+ T cell infiltration and function. Further CD8+ T cell depletion experiments confirmed that CD8+ T cells were required for the antitumor activity of ApoA1. In vitro, ApoA1 peptide L-4F can directly potentiate the antitumor activity of CD8+ T cells via HIF-1α-mediated glycolysis pathway. Mechanistically, we found that ApoA1 reduced the ubiquitination degradation pathway of HIF-1α by down-regulating FIH1, further maintain the stability of HIF-1α protein and signaling activation. Lastly, tumor-bearing A1TG mice showed significant sensitivity to anti-PD-1 therapy, with retarded tumor growth and increased tumor necrosis.Conclusion/ImplicationsOur data demonstrated the critical roles of ApoA1 in remodeling immune microenvironment and enhancing CD8+ T cell immune functions via HIF-1α-mediated glycolysis, which supports the clinical investigation for a combination of ApoA1 supplementation and anti-PD-1 therapy in tumors.