Low-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8+T cells.

PURPOSE: Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy. METHODS: We tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy. RESULTS: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1. CONCLUSION: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.

Gallic acid induces T-helper-1-like Treg cells and strengthens immune checkpoint blockade efficacy.

BACKGROUND: Foxp3+ regulatory T (Treg) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting Treg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers. METHODS: We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and Treg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in Treg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy. RESULTS: Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of Treg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen Treg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8+ T cells' production of IFN-γ and limited tumor growth. CONCLUSION: Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3lo Treg cells.

Cutting Edge: Inhibition of Glycogen Synthase Kinase 3 Activity Induces the Generation and Enhanced Suppressive Function of Human IL-10+ FOXP3+-Induced Regulatory T Cells.

IL-10 is critical for Foxp3+ regulatory T cell (Tregs)-mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10+ FOXP3+-induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10+ FOXP3+ iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10+ iTregs exhibit enhanced suppressive function in both IL-10-dependent and -independent manners. The enhanced suppressive function of IL-10+ Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10+ FOXP3+ Tregs for immunotherapies.