Low-dose Anti-VEGFR2 Therapy Promotes Anti-tumor Immunity in Lung Adenocarcinoma by Down-regulating the Expression of Layilin on Tumor-infiltrating CD8T Cells

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2022 Oct 19

PMID 36260222

Authors

Biaolong Yang

Biaolong Deng

Xiao-Dong Jiao

Bao-Dong Qin

Yi Lu

Weiqi Zhang

Yixian Guo

Shiqi Chen

Dan Li

Bin Li

Yuan-Sheng Zang

Affiliations

Soon will be listed here.

Abstract

Purpose: Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8T 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 CD8T cells by flow cytometry. CD8T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8T 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 CD8T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYNCD8T 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 CD8T 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.

Citing Articles

Missense mutations of GPER1 in breast invasive carcinoma: Exploring gene expression, signal transduction and immune cell infiltration with insights from cellular pharmacology.

Zhang Y, Du C, Zhang S, Yu H, Mo H, Yang Q Biomed Rep. 2024; 22(2):22.

PMID: 39720300 PMC: 11668130. DOI: 10.3892/br.2024.1900.

The prognostic value of LAYN in HPV-related head and neck squamous cell carcinoma and its influence on immune cell infiltration.

Chen Q, Chen J, Lu Z, Nian R, Li W, Yao Z Discov Oncol. 2024; 15(1):57.

PMID: 38430385 PMC: 10908921. DOI: 10.1007/s12672-024-00913-5.

Adjusting the dose of traditional drugs combined with immunotherapy: reshaping the immune microenvironment in lung cancer.

Wang L, Du C, Jiang B, Chen L, Wang Z Front Immunol. 2023; 14:1256740.

PMID: 37901223 PMC: 10600379. DOI: 10.3389/fimmu.2023.1256740.

References

Huang Y, Yuan J, Righi E, Kamoun W, Ancukiewicz M, Nezivar J . Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012; 109(43):17561-6. PMC: 3491458. DOI: 10.1073/pnas.1215397109. View

Hato T, Zhu A, Duda D . Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016; 8(3):299-313. PMC: 5619018. DOI: 10.2217/imt.15.126. View

Morgensztern D, Herbst R . Nivolumab and Pembrolizumab for Non-Small Cell Lung Cancer. Clin Cancer Res. 2016; 22(15):3713-7. DOI: 10.1158/1078-0432.CCR-15-2998. View

Sanmamed M, Chen L . A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization. Cell. 2018; 175(2):313-326. PMC: 6538253. DOI: 10.1016/j.cell.2018.09.035. View

Kim C, Jang M, Kim Y, Leem G, Kim K, Lee H . VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Sci Immunol. 2019; 4(41). DOI: 10.1126/sciimmunol.aay0555. View

De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C . Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 2016; 45(5):1135-1147. PMC: 5119953. DOI: 10.1016/j.immuni.2016.10.021. View

Kim Y, West G, Ray G, Kessler S, Petrey A, Fiocchi C . Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Matrix Biol. 2017; 66:93-109. PMC: 5845474. DOI: 10.1016/j.matbio.2017.09.003. View

Hodi F, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T . Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014; 2(7):632-42. PMC: 4306338. DOI: 10.1158/2326-6066.CIR-14-0053. View

Bengsch B, Ohtani T, Khan O, Setty M, Manne S, OBrien S . Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity. 2018; 48(5):1029-1045.e5. PMC: 6010198. DOI: 10.1016/j.immuni.2018.04.026. View

10.

Zhao X, Subramanian S . Intrinsic Resistance of Solid Tumors to Immune Checkpoint Blockade Therapy. Cancer Res. 2017; 77(4):817-822. DOI: 10.1158/0008-5472.CAN-16-2379. View

11.

Chang C, Qiu J, OSullivan D, Buck M, Noguchi T, Curtis J . Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015; 162(6):1229-41. PMC: 4864363. DOI: 10.1016/j.cell.2015.08.016. View

12.

Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J . Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011; 30(1):83-95. DOI: 10.1007/s10555-011-9281-4. View

13.

Weng L, Smits P, Wauters J, Merregaert J . Molecular cloning and characterization of human chondrolectin, a novel type I transmembrane protein homologous to C-type lectins. Genomics. 2002; 80(1):62-70. DOI: 10.1006/geno.2002.6806. View

14.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View

15.

de Almeida P, Mak J, Hernandez G, Jesudason R, Herault A, Javinal V . Anti-VEGF Treatment Enhances CD8 T-cell Antitumor Activity by Amplifying Hypoxia. Cancer Immunol Res. 2020; 8(6):806-818. DOI: 10.1158/2326-6066.CIR-19-0360. View

16.

Miller B, Sen D, Al Abosy R, Bi K, Virkud Y, LaFleur M . Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3):326-336. PMC: 6673650. DOI: 10.1038/s41590-019-0312-6. View

17.

Allen E, Jabouille A, Rivera L, Lodewijckx I, Missiaen R, Steri V . Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017; 9(385). PMC: 5554432. DOI: 10.1126/scitranslmed.aak9679. View

18.

Adachi T, Arito M, Suematsu N, Kamijo-Ikemori A, Omoteyama K, Sato T . Roles of layilin in TNF-α-induced epithelial-mesenchymal transformation of renal tubular epithelial cells. Biochem Biophys Res Commun. 2015; 467(1):63-9. DOI: 10.1016/j.bbrc.2015.09.121. View

19.

Lanitis E, Irving M, Coukos G . Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol. 2015; 33:55-63. PMC: 4896929. DOI: 10.1016/j.coi.2015.01.011. View

20.

Lee S, Lee S, Lee W, Yoo J, Sun J, Lee J . Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors. Invest New Drugs. 2017; 35(6):782-790. PMC: 5694508. DOI: 10.1007/s10637-017-0463-y. View