Low serum apolipoprotein A1 impairs antitumor immunity of CD8+ T cells via the HIF-1α-glycolysis pathway

An immunosuppressive microenvironment plays a major role in 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 the serum ApoA1 level and 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 tissues, the low serum ApoA1 group showed increased CD163+ macrophages 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 were also found in tumor-bearing ApoA1-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 ApoA1 mimetic peptide L-4F directly potentiated the antitumor activity of CD8+ T cells via the HIF-1α-mediated glycolysis pathway. Mechanistically, ApoA1 suppressed the ubiquitin-mediated degradation pathway of HIF-1α protein by downregulating HIF-1α subunit α inhibitor, which maintained the stability of HIF-1α protein and HIF-1α signal activation. Tumor-bearing ApoA1 transgenic mice showed an increased response to anti-PD-1 therapy with inhibited tumor growth and increased tumor necrosis. Here, the data demonstrate the critical roles of ApoA1 in enhancing CD8+ T cell immune functions via HIF-1α-mediated glycolysis, which supports clinical investigation of combined ApoA1 supplementation and anti-PD-1 therapy for tumors.