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Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8 + T cells in the tumor microenvironment.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2018 Oct 11; Vol. 6 (1), pp. 106. Date of Electronic Publication: 2018 Oct 11. - Publication Year :
- 2018
-
Abstract
- Background: Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers.<br />Methods: We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry.<br />Results: Within the tumor microenvironment, both PD-L1 expression and CD8 <superscript>+</superscript> T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA <superscript>-</superscript> FOXP3 <superscript>high</superscript> CD4 <superscript>+</superscript> cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8 <superscript>+</superscript> T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2 <superscript>+</superscript> eTreg cell proliferation, and this effect could be inhibited by RAM.<br />Conclusions: This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.
- Subjects :
- Aged
Antibodies, Monoclonal, Humanized
CD8-Positive T-Lymphocytes immunology
Female
Humans
Male
Middle Aged
Programmed Cell Death 1 Receptor immunology
Stomach Neoplasms immunology
T-Lymphocytes, Regulatory immunology
Tumor Microenvironment immunology
Ramucirumab
Antibodies, Monoclonal therapeutic use
Antineoplastic Agents therapeutic use
CD8-Positive T-Lymphocytes drug effects
Stomach Neoplasms drug therapy
T-Lymphocytes, Regulatory drug effects
Tumor Microenvironment drug effects
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 6
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 30314524
- Full Text :
- https://doi.org/10.1186/s40425-018-0403-1