biostudies-literatureYang BScience and Technology Commission of Shanghai MunicipalityClinical Trial Funding of Shanghai Changzheng HospitalNational Natural Science Foundation of China1297-1309https://www.ebi.ac.uk/biostudies/studies/S-EPMC9747853biostudies-literatureUnknown45(6)<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Cellular oncology (Dordrecht)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.PMC974785381702249, 201720Y11914400, 20222020YLCYJ-Z03, 202082172710, 2021Deng BZhang WGuo YLi DLu YYang BLi BJiao XDChen SQin BDZang YSfalseLow-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8⁺T cells.<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.2022-01-01T00:00:00Z2022 Dec2025-04-18T19:20:38.024Z2025-04-07T07:01:15.017ZS-EPMC97478533626022210.1007/s13402-022-00718-0