期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 6, 期 -, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1186/s40425-018-0403-1
关键词
Regulatory T cells; PD-1; Ramucirumab; VEGFR2; Gastric cancer
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17H06162, 16 K15551, 17 J09900, 17 K18388]
- Project for Cancer Research by Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development (AMED) [16cm0106301h0002]
- National Cancer Center Research and Development Fund [28-A-7]
- Naito Foundation
- Takeda Foundation
- SGH Foundation
- Eli Lilly Japan KK
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. 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. Results: Within the tumor microenvironment, both PD-L1 expression and CD8(+) T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA-FOXP3(high)CD4(+) cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8(+) 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(+) eTreg cell proliferation, and this effect could be inhibited by RAM. 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.
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