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. [ABSTRACT FROM AUTHOR]