Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells

被引：266

作者：

Horikawa, Naoki ^{[1
]}

Abiko, Kaoru ^{[1
]}

Matsumura, Noriomi ^{[1
]}

Hamanishi, Junzo ^{[1
]}

Baba, Tsukasa ^{[1
]}

Yamaguchi, Ken ^{[1
]}

Yoshioka, Yumiko ^{[1
]}

Koshiyama, Masafumi ^{[1
]}

Konishi, Ikuo ^{[1
]}

机构：

[1] Kyoto Univ, Dept Gynecol & Obstet, Grad Sch Med, Kyoto, Japan

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 02期

关键词：

T-CELLS; VEGF; LYMPHOCYTES; SURVIVAL; ASCITES; PATHWAY;

D O I：

10.1158/1078-0432.CCR-16-0387

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Purpose: High VEGF expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSC), in ovarian cancer. Experimental Design: High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and IHC for VEGF, CD8, and CD33. VEG Freceptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1(+) MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. In addition, the therapeutic effects of anti-Gr-1 antibodies were examined. Results: Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocyte-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8(+) T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8(+) T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment. Conclusions: VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587- 99. (C) 2016 AACR.

引用

页码：587 / 599

页数：13

共 50 条

[1]

IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer [J].

Abiko, K. ;

Matsumura, N. ;

Hamanishi, J. ;

Horikawa, N. ;

Murakami, R. ;

Yamaguchi, K. ;

Yoshioka, Y. ;

Baba, T. ;

Konishi, I. ;

Mandai, M. .

BRITISH JOURNAL OF CANCER, 2015, 112 (09) :1501-1509

[2]

PD-L1 on Tumor Cells Is Induced in Ascites and Promotes Peritoneal Dissemination of Ovarian Cancer through CTL Dysfunction [J].

Abiko, Kaoru ;

Mandai, Masaki ;

Hamanishi, Junzo ;

Yoshioka, Yumiko ;

Matsumura, Noriomi ;

Baba, Tsukasa ;

Yamaguchi, Ken ;

Murakami, Ryusuke ;

Yamamoto, Ayaka ;

Kharma, Budiman ;

Kosaka, Kenzo ;

Konishi, Ikuo .

CLINICAL CANCER RESEARCH, 2013, 19 (06) :1363-1374

[3]

Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[4]

Ovarian cancer tumor infiltrating T-regulatory (Treg) cells are associated with a metastatic phenotype [J].

Barnett, Jason C. ;

Bean, Sarah M. ;

Whitaker, Regina S. ;

Kondoh, Eiji ;

Baba, Tsukasa ;

Fujii, Shingo ;

Marks, Jeffrey R. ;

Dressman, Holly K. ;

Murphy, Susan K. ;

Berchuck, Andrew .

GYNECOLOGIC ONCOLOGY, 2010, 116 (03) :556-562

[5]

Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[6]

Cesar AC, 2010, J EXP MED, V207, P2439

[7]

Chang SH, 2014, P NATL ACAD SCI USA, V111, P1

[8]

Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset [J].

Choe, SE ;

Boutros, M ;

Michelson, AM ;

Church, GM ;

Halfon, MS .

GENOME BIOLOGY, 2005, 6 (02)

[9]

Latest research and treatment of advanced-stage epithelial ovarian cancer [J].

Coleman, Robert L. ;

Monk, Bradley J. ;

Sood, Anil K. ;

Herzog, Thomas J. .

NATURE REVIEWS CLINICAL ONCOLOGY, 2013, 10 (04) :211-224

[10]

Myeloid-Derived Suppressor Cells Enhance Stemness of Cancer Cells by Inducing MicroRNA101 and Suppressing the Corepressor CtBP2 [J].

Cui, Tracy X. ;

Kryczek, Ilona ;

Zhao, Lili ;

Zhao, Ende ;

Kuick, Rork ;

Roh, Michael H. ;

Vatan, Linda ;

Szeliga, Wojciech ;

Mao, Yujun ;

Thomas, Dafydd G. ;

Kotarski, Jan ;

Tarkowski, Rafal ;

Wicha, Max ;

Cho, Kathleen ;

Giordano, Thomas ;

Liu, Rebecca ;

Zou, Weiping .

IMMUNITY, 2013, 39 (03) :611-U222

← 1 2 3 4 5 →