Advertisement

Targeting the tumour microenvironment in ovarian cancer

  • Jean M. Hansen
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, USA
    Search for articles by this author
  • Robert L. Coleman
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, USA
    Search for articles by this author
  • Anil K. Sood
    Correspondence
    Corresponding author: 1155 Pressler St, Unit 1362, Houston, TX 77030, USA.
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, USA

    Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, USA

    Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, USA
    Search for articles by this author
Published:February 02, 2016DOI:https://doi.org/10.1016/j.ejca.2015.12.016

      Abstract

      The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype.
      Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hanahan D.
        • Weinberg R.A.
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Pietras K.
        • Ostman A.
        Hallmarks of cancer: interactions with the tumor stroma.
        Exp Cell Res. 2010; 316: 1324-1331
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2015.
        CA Cancer J Clin. 2015; 65: 5-29
        • Torre L.A.
        • Bray F.
        • Siegel R.L.
        • Ferlay J.
        • Lortet-Tieulent J.
        • Jemal A.
        Global cancer statistics, 2012.
        CA Cancer J Clin. 2015;
        • Morgan Jr., R.J.
        • Alvarez R.D.
        • Armstrong D.K.
        • Boston B.
        • Burger R.A.
        • Chen L.
        • et al.
        Epithelial ovarian cancer.
        J Natl Compr Canc Netw. 2011; 9: 82-113
        • Bowtell D.D.
        The genesis and evolution of high-grade serous ovarian cancer.
        Nat Rev Cancer. 2010; 10: 803-808
        • Kindelberger D.W.
        • Lee Y.
        • Miron A.
        • Hirsch M.S.
        • Feltmate C.
        • Medeiros F.
        • et al.
        Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.
        Am J Surg Pathol. 2007; 31: 161-169
        • Levanon K.
        • Crum C.
        • Drapkin R.
        New insights into the pathogenesis of serous ovarian cancer and its clinical impact.
        J Clin Oncol. 2008; 26: 5284-5293
        • Flesken-Nikitin A.
        • Hwang C.
        • Cheng C.
        • Michurina T.V.
        • Enikolopov G.
        • Nikitin A.Y.
        Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.
        Nature. 2013; 495: 241-245
        • Pradeep S.
        • Kim S.W.
        • Wu S.Y.
        • Nishimura M.
        • Chaluvally-Raghavan P.
        • Miyake T.
        • et al.
        Hematogenous metastasis of ovarian cancer: rethinking mode of spread.
        Cancer Cell. 2014; 26: 77-91
        • Phillips K.G.
        • Ruiz Velasco C.
        • Li J.
        • Kolatkar A.
        • Luttgen M.
        • Bethel K.
        • et al.
        Optical quantification of cellular mass, volume, and density of circulating tumor cells identified in an ovarian cancer patient.
        Front Oncol. 2012; 2: 72
        • Nieman K.M.
        • Kenny H.A.
        • Penicka C.V.
        • Ladanyi A.
        • Buell-Gutbrod R.
        • Zillhardt M.R.
        • et al.
        Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.
        Nat Med. 2011; 17: 1498-1503
        • Tomasek J.J.
        • Gabbiani G.
        • Hinz B.
        • Chaponnier C.
        • Brown R.A.
        Myofibroblasts and mechano-regulation of connective tissue remodelling.
        Nat Rev Mol Cell Biol. 2002; 3: 349-363
        • Chang H.Y.
        • Chi J.T.
        • Dudoit S.
        • Bondre C.
        • van de Rijn M.
        • Botstein D.
        • et al.
        Diversity, topographic differentiation, and positional memory in human fibroblasts.
        Proc Natl Acad Sci U S A. 2002; 99: 12877-12882
        • Kalluri R.
        • Zeisberg M.
        Fibroblasts in cancer.
        Nat Rev Cancer. 2006; 6: 392-401
        • Gabbiani G.
        • Ryan G.B.
        • Majne G.
        Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction.
        Experientia. 1971; 27: 549-550
        • Sieweke M.H.
        • Thompson N.L.
        • Sporn M.B.
        • Bissell M.J.
        Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta.
        Science. 1990; 248: 1656-1660
        • Cai J.
        • Tang H.
        • Xu L.
        • Wang X.
        • Yang C.
        • Ruan S.
        • et al.
        Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness.
        Carcinogenesis. 2012; 33: 20-29
        • Desmouliere A.
        • Redard M.
        • Darby I.
        • Gabbiani G.
        Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar.
        Am J Pathol. 1995; 146: 56-66
        • Rasanen K.
        • Vaheri A.
        Activation of fibroblasts in cancer stroma.
        Exp Cell Res. 2010; 316: 2713-2722
        • Dolberg D.S.
        • Hollingsworth R.
        • Hertle M.
        • Bissell M.J.
        Wounding and its role in RSV-mediated tumor formation.
        Science. 1985; 230: 676-678
        • Dvorak H.F.
        Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
        N Engl J Med. 1986; 315: 1650-1659
        • Cirri P.
        • Chiarugi P.
        Cancer associated fibroblasts: the dark side of the coin.
        Am J Cancer Res. 2011; 1: 482-497
        • McAnulty R.J.
        Fibroblasts and myofibroblasts: their source, function and role in disease.
        Int J Biochem Cell Biol. 2007; 39: 666-671
        • Fukumura D.
        • Xavier R.
        • Sugiura T.
        • Chen Y.
        • Park E.
        • Lu N.
        • et al.
        Tumor induction of VEGF promoter activity in stromal cells.
        Cell. 1998; 94: 715-725
        • Granot D.
        • Addadi Y.
        • Kalchenko V.
        • Harmelin A.
        • Kunz-Schughart L.A.
        • Neeman M.
        In vivo imaging of the systemic recruitment of fibroblasts to the angiogenic rim of ovarian carcinoma tumors.
        Cancer Res. 2007; 67: 9180-9189
        • Jeon E.S.
        • Moon H.J.
        • Lee M.J.
        • Song H.Y.
        • Kim Y.M.
        • Cho M.
        • et al.
        Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells.
        Stem Cells. 2008; 26: 789-797
        • Heller E.
        • Hurchla M.A.
        • Xiang J.
        • Su X.
        • Chen S.
        • Schneider J.
        • et al.
        Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.
        Cancer Res. 2012; 72: 897-907
        • Harris L.G.
        • Samant R.S.
        • Shevde L.A.
        Hedgehog signaling: networking to nurture a promalignant tumor microenvironment.
        Mol Cancer Res. 2011; 9: 1165-1174
        • Dierks C.
        • Grbic J.
        • Zirlik K.
        • Beigi R.
        • Englund N.P.
        • Guo G.
        • et al.
        Essential role of stromally induced hedgehog signaling in B-cell malignancies.
        Nat Med. 2007; 13: 944-951
        • Zhang Y.
        • Tang H.
        • Cai J.
        • Zhang T.
        • Guo J.
        • Feng D.
        • et al.
        Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion.
        Cancer Lett. 2011; 303: 47-55
        • Schauer I.G.
        • Sood A.K.
        • Mok S.
        • Liu J.
        Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer.
        Neoplasia. 2011; 13: 393-405
        • Gilead A.
        • Meir G.
        • Neeman M.
        The role of angiogenesis, vascular maturation, regression and stroma infiltration in dormancy and growth of implanted MLS ovarian carcinoma spheroids.
        Int J Cancer. 2004; 108: 524-531
        • Mhawech-Fauceglia P.
        • Yan L.
        • Sharifian M.
        • Ren X.
        • Liu S.
        • Kim G.
        • et al.
        Stromal expression of fibroblast activation protein alpha (FAP) predicts platinum resistance and shorter recurrence in patients with epithelial ovarian cancer.
        Cancer Microenviron. 2014;
        • Itamochi H.
        • Oumi N.
        • Oishi T.
        • Taniguchi F.
        • Shoji T.
        • Fujiwara H.
        • et al.
        Fibroblast growth factor receptor 2 is associated with poor overall survival in clear cell carcinoma of the ovary and may be a novel therapeutic approach.
        Int J Gynecol Cancer. 2015; 25: 570-576
        • Yao Q.
        • Qu X.
        • Yang Q.
        • Wei M.
        • Kong B.
        CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer.
        Oncol Rep. 2009; 22: 541-548
        • The Cancer Genome Atlas Research Network
        Integrated genomic analyses of ovarian carcinoma.
        Nature. 2011; 474: 609-615
        • Kiaris H.
        • Chatzistamou I.
        • Trimis G.
        • Frangou-Plemmenou M.
        • Pafiti-Kondi A.
        • Kalofoutis A.
        Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis.
        Cancer Res. 2005; 65: 1627-1630
        • Wernert N.
        • Locherbach C.
        • Wellmann A.
        • Behrens P.
        • Hugel A.
        Presence of genetic alterations in microdissected stroma of human colon and breast cancers.
        Anticancer Res. 2001; 21: 2259-2264
        • Hawsawi N.M.
        • Ghebeh H.
        • Hendrayani S.
        • Tulbah A.
        • Al-Eid M.
        • Al-Tweigeri T.
        • et al.
        Breast carcinoma-associated fibroblasts and their counterparts display neoplastic-specific changes.
        Cancer Res. 2008; 68: 2717-2725
        • Ledermann J.A.
        • Hackshaw A.
        • Kaye S.
        • Jayson G.
        • Gabra H.
        • McNeish I.
        • et al.
        Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.
        J Clin Oncol. 2011; 29: 3798-3804
        • Du Bois A.
        • Kristensen G.
        • Ray-Coquard I.
        • Reuss A.
        • Pignata S.
        • Colombo N.
        • et al.
        AGO-OVAR 12: a randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy+/−nintedanib for advanced ovarian cancer.
        Int J Gynecol Cancer. 2013; 23.8
        • Bergers G.
        • Hanahan D.
        Modes of resistance to anti-angiogenic therapy.
        Nat Rev Cancer. 2008; 8: 592-603
        • Choi H.J.
        • Armaiz Pena G.N.
        • Pradeep S.
        • Cho M.S.
        • Coleman R.L.
        • Sood A.K.
        Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches.
        Cancer Metastasis Rev. 2015; 34: 19-40
        • Hanahan D.
        • Folkman J.
        Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
        Cell. 1996; 86: 353-364
        • Folkman J.
        Anti-angiogenesis: new concept for therapy of solid tumors.
        Ann Surg. 1972; 175: 409-416
        • Folkman J.
        Tumor angiogenesis: therapeutic implications.
        N Engl J Med. 1971; 285: 1182-1186
        • Brem S.
        • Brem H.
        • Folkman J.
        • Finkelstein D.
        • Patz A.
        Prolonged tumor dormancy by prevention of neovascularization in the vitreous.
        Cancer Res. 1976; 36: 2807-2812
        • Holmgren L.
        • O'Reilly M.S.
        • Folkman J.
        Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.
        Nat Med. 1995; 1: 149-153
        • Kerbel R.S.
        Tumor angiogenesis: past, present and the near future.
        Carcinogenesis. 2000; 21: 505-515
        • Holash J.
        • Maisonpierre P.C.
        • Compton D.
        • Boland P.
        • Alexander C.R.
        • Zagzag D.
        • et al.
        Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.
        Science. 1999; 284: 1994-1998
        • Folberg R.
        • Hendrix M.J.
        • Maniotis A.J.
        Vasculogenic mimicry and tumor angiogenesis.
        Am J Pathol. 2000; 156: 361-381
        • Maniotis A.J.
        • Folberg R.
        • Hess A.
        • Seftor E.A.
        • Gardner L.M.G.
        • Pe'er J.
        • et al.
        Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.
        Am J Pathol. 1999; 155: 739-752
        • Carmeliet P.
        • Jain R.K.
        Angiogenesis in cancer and other diseases.
        Nature. 2000; 407: 249-257
        • Kim K.J.
        • Li B.
        • Winer J.
        • Armanini M.
        • Gillett N.
        • Phillips H.S.
        • et al.
        Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.
        Nature. 1993; 362: 841-844
        • Ferrara N.
        VEGF as a therapeutic target in cancer.
        Oncology. 2005; 69: 11-16
        • Ferrara N.
        • Kerbel R.S.
        Angiogenesis as a therapeutic target.
        Nature. 2005; 438: 967-974
        • Kerbel R.S.
        Tumor angiogenesis.
        N Engl J Med. 2008; 358: 2039-2049
        • Semenza G.L.
        Targeting HIF-1 for cancer therapy.
        Nat Rev Cancer. 2003; 3: 721-732
        • Tammela T.
        • Zarkada G.
        • Wallgard E.
        • Murtomaki A.
        • Suchting S.
        • Wirzenius M.
        • et al.
        Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.
        Nature. 2008; 454: 656-660
        • Gerber H.P.
        • Malik A.K.
        • Solar G.P.
        • Sherman D.
        • Liang X.H.
        • Meng G.
        • et al.
        VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism.
        Nature. 2002; 417: 954-958
        • Spannuth W.A.
        • Nick A.M.
        • Jennings N.B.
        • Armaiz Pena G.N.
        • Mangala L.S.
        • Danes C.G.
        • et al.
        Functional significance of VEGFR-2 on ovarian cancer cells.
        Int J Cancer. 2009; 124: 1045-1053
        • Hennessy B.T.
        • Coleman R.L.
        • Markman M.
        Ovarian cancer.
        Lancet. 2009; 374: 1371-1382
        • Stockler M.R.
        • Hilpert F.
        • Friedlander M.
        • King M.T.
        • Wenzel L.
        • Lee C.K.
        • et al.
        Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer.
        J Clin Oncol. 2014; 32: 1309-1316
        • Pujade-Lauraine E.
        • Hilpert F.
        • Weber B.
        • Reuss A.
        • Poveda A.
        • Kristensen G.
        • et al.
        Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial.
        J Clin Oncol. 2014; 32: 1302-1308
        • Burger R.A.
        • Brady M.F.
        • Bookman M.A.
        • Fleming G.F.
        • Monk B.J.
        • Huang H.
        • et al.
        Incorporation of bevacizumab in the primary treatment of ovarian cancer.
        N Engl J Med. 2011; 365: 2473-2483
        • Perren T.J.
        • Swart A.M.
        • Pfisterer J.
        • Ledermann J.A.
        • Pujade-Lauraine E.
        • Kristensen G.
        • et al.
        A phase 3 trial of bevacizumab in ovarian cancer.
        N Engl J Med. 2011; 365: 2484-2496
        • Jain R.K.
        Molecular regulation of vessel maturation.
        Nat Med. 2003; 9: 685-693
        • Bergers G.
        • Song S.
        • Meyer-Morse N.
        • Bergsland E.
        • Hanahan D.
        Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.
        J Clin Invest. 2003; 111: 1287-1295
        • Erber R.
        • Thurnher A.
        • Katsen A.D.
        • Groth G.
        • Kerger H.
        • Hammes H.P.
        • et al.
        Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms.
        FASEB J. 2004; 18: 338-340
        • Jo N.
        • Mailhos C.
        • Ju M.
        • Cheung E.
        • Bradley J.
        • Nishijima K.
        • et al.
        Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization.
        Am J Pathol. 2006; 168: 2036-2053
        • Matulonis U.A.
        • Berlin S.
        • Ivy P.
        • Tyburski K.
        • Krasner C.
        • Zarwan C.
        • et al.
        Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.
        J Clin Oncol. 2009; 27: 5601-5606
        • Raja F.A.
        • Griffin C.L.
        • Qian W.
        • Hirte H.
        • Parmar M.K.
        • Swart A.M.
        • et al.
        Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer.
        Br J Cancer. 2011; 105: 884-889
        • Ledermann J.A.
        • Perren T.J.
        • Raja F.A.
        Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. ESMO.
        2013 (Abstract No. 10)
        • Liu J.F.
        • Barry W.T.
        • Birrer M.
        • Lee J.M.
        • Buckanovich R.J.
        • Fleming G.F.
        • et al.
        Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
        Lancet Oncol. 2014; 15: 1207-1214
        • Matei D.
        • Sill M.W.
        • Lankes H.A.
        • DeGeest K.
        • Bristow R.E.
        • Mutch D.
        • et al.
        Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial.
        J Clin Oncol. 2011; 29: 69-75
        • Herzog T.J.
        • Scambia G.
        • Kim B.G.
        • Lhomme C.
        • Markowska J.
        • Ray-Coquard I.
        • et al.
        A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma.
        Gynecol Oncol. 2013; 130: 25-30
        • Friedlander M.
        • Hancock K.C.
        • Rischin D.
        • Messing M.J.
        • Stringer C.A.
        • Matthys G.M.
        • et al.
        A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer.
        Gynecol Oncol. 2010; 119: 32-37
        • du Bois A.
        • Floquet A.
        • Kim J.W.
        • Rau J.
        • del Campo J.M.
        • Friedlander M.
        • et al.
        Incorporation of pazopanib in maintenance therapy of ovarian cancer.
        J Clin Oncol. 2014; 32: 3374-3382
        • Holash J.
        • Davis S.
        • Papadopoulos N.
        • Croll S.D.
        • Ho L.
        • Russell M.
        • et al.
        VEGF-Trap: a VEGF blocker with potent antitumor effects.
        Proc Natl Acad Sci U S A. 2002; 99: 11393-11398
        • Coleman R.L.
        • Duska L.R.
        • Ramirez P.T.
        • Heymach J.V.
        • Kamat A.A.
        • Modesitt S.C.
        • et al.
        Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.
        Lancet Oncol. 2011; 12: 1109-1117
        • Gotlieb W.H.
        • Amant F.
        • Advani S.
        • Goswarni C.
        • Hirte H.
        • Provencher D.
        • et al.
        Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study.
        Lancet Oncol. 2012; 13: 154-162
        • Li J.L.
        • Harris A.L.
        Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications.
        Front Biosci (Landmark Ed). 2009; 14: 3094-3110
        • Li J.L.
        • Sainson R.C.A.
        • Oon C.E.
        • Turley H.
        • Leek R.
        • Sheldon H.
        • et al.
        DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.
        Cancer Res. 2011; 71: 6073-6083
        • Condeelis J.
        • Pollard J.W.
        Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.
        Cell. 2006; 124: 263-266
        • Scavelli C.
        • Nico B.
        • Cirulli T.
        • Ria R.
        • Di Pietro G.
        • Mangieri D.
        • et al.
        Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma.
        Oncogene. 2008; 27: 663-674
        • Negus R.P.
        • Stamp G.W.
        • Hadley J.
        • Balkwill F.R.
        Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines.
        Am J Pathol. 1997; 150: 1723-1734
        • Coussens L.M.
        • Werb Z.
        Inflammation and cancer.
        Nature. 2002; 420: 860-867
        • Balkwill F.
        • Mantovani A.
        Inflammation and cancer: back to Virchow?.
        Lancet. 2001; 357: 539-545
        • Parkin D.M.
        The global health burden of infection-associated cancers in the year 2002.
        Int J Cancer. 2002; 118: 3030-3044
        • Ekbom A.
        • Helmick C.
        • Zack M.
        • Adami H.O.
        Ulcerative colitis and colorectal cancer. a population-based study.
        N Engl J Med. 1990; 323: 1228-1233
        • Grivennikov S.
        • Karin E.
        • Terzic J.
        • Mucida D.
        • Yu G.Y.
        • Vallabhapurapu S.
        • et al.
        IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer.
        Cancer Cell. 2009; 15: 103-113
        • Balkwill F.
        • Charles K.A.
        • Mantovani A.
        Smoldering and polarized inflammation in the initiation and promotion of malignant disease.
        Cancer Cell. 2005; 7: 211-217
        • Hanahan D.
        • Coussens L.M.
        Accessories to the crime: functions of cells recruited to the tumor microenvironment.
        Cancer Cell. 2012; 21: 309-322
        • Rosenberg S.A.
        IL-2: the first effective immunotherapy for human cancer.
        J Immunol. 2014; 192: 5451-5458
        • Rosenberg S.A.
        • Spiess P.
        • Lafreniere R.
        A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.
        Science. 1986; 233: 1318-1321
        • Dillman R.O.
        • Barth N.M.
        • Oldham R.K.
        • Cohen R.J.
        • Minor D.R.
        • Birch R.
        • et al.
        Continuous interleukin-2 and tumor-infiltrating lymphocytes as treatment of advanced melanoma. a national biotherapy study group trial.
        Cancer. 1991; 68: 1-8
        • Rosenberg S.A.
        • Dudley M.E.
        Adoptive cell therapy for the treatment of patients with metastatic melanoma.
        Curr Opin Immunol. 2009; 21: 233-240
        • Kandalaft L.E.
        • Powell D.J.
        • Singh N.
        • Coukos G.
        Immunotherapy for ovarian cancer: what's next?.
        J Clin Oncol. 2011; 29: 925-933
        • Zhang L.
        • Conejo-Garcia J.R.
        • Katsaros D.
        • Gimotty P.A.
        • Massobrio M.
        • Regnani G.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N Engl J Med. 2003; 348: 203-213
        • Halpern A.C.
        • Schuchter L.M.
        Prognostic models in melanoma.
        Semin Oncol. 1997; 24: S2-7
        • Naito Y.
        • Saito K.
        • Shiiba K.
        • Ohuchi A.
        • Saigenji K.
        • Nagura H.
        • et al.
        CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.
        Cancer Res. 1998; 58: 3491-3494
        • Marrogi A.J.
        • Munshi A.
        • Merogi A.J.
        • Ohadike Y.
        • El-Habashi A.
        • Marrogi O.L.
        • et al.
        Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma.
        Int J Cancer. 1997; 74: 492-501
        • Vesalainen S.
        • Lipponen P.
        • Talja M.
        • Syrjanen K.
        Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma.
        Eur J Cancer. 1994; 30A: 1797-1803
        • Nakano O.
        • Sato M.
        • Naito Y.
        • Suzuki K.
        • Orikasa S.
        • Aizawa M.
        • et al.
        Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity.
        Cancer Res. 2001; 61: 5132-5136
        • Schumacher K.
        • Haensch W.
        • Roefzaad C.
        • Schlag P.M.
        Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas.
        Cancer Res. 2001; 61: 3932-3936
        • Adams S.F.
        • Levine D.A.
        • Cadungog M.G.
        • Hammond R.
        • Facciabene A.
        • Olvera N.
        • et al.
        Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer.
        Cancer. 2009; 115: 2891-2902
        • Vlad A.M.
        • Budiu R.A.
        • Lenzer D.E.
        • Wang Y.
        • Thaller J.A.
        • Colonello K.
        • et al.
        A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer.
        Cancer Immunol Immunother. 2010; 59: 293-301
        • Fujita K.
        • Ikarashi H.
        • Takakuwa K.
        • Kodama S.
        • Tokunga A.
        • Takahashi T.
        • et al.
        Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes.
        Clin Cancer Res. 1995; 1: 501-507
        • Hodi F.S.
        • Mihm M.C.
        • Soiffer R.J.
        • Haluska F.G.
        • Butler M.
        • Seiden M.V.
        • et al.
        Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
        Proc Natl Acad Sci U S A. 2003; 100: 4712-4717
        • Hodi F.S.
        • Butler M.
        • Oble D.A.
        • Seiden M.V.
        • Haluska G.F.
        • Kruse A.
        • et al.
        Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
        Proc Natl Acad Sci U S A. 2008; 105: 3005-3010
        • Dong H.
        • Zhu G.
        • Tamada K.
        • Chen L.
        B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.
        Nat Med. 1999; 5: 1365-1369
        • Freeman G.J.
        • Long A.J.
        • Iwai Y.
        • Bourque K.
        • Chernova T.
        • Nishimura H.
        • et al.
        Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
        J Exp Med. 2000; 192: 1027-1034
        • Topalian S.L.
        • Drake C.G.
        • Pardoll D.M.
        Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.
        Curr Opin Immunol. 2012; 24: 207-212
        • Dong H.
        • Strome S.E.
        • Salomao D.R.
        • Tamura H.
        • Hirano F.
        • Flies D.B.
        • et al.
        Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
        Nat Med. 2002; 8: 793-800
        • Brahmer J.R.
        • Tykodi S.S.
        • Chow L.Q.M.
        • Hwu W.J.
        • Topalian S.L.
        • Hwu P.
        • et al.
        Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
        N Engl J Med. 2012; 366: 2455-2465
        • Topalian S.L.
        • Hodi F.S.
        • Brahmer J.R.
        • Gettinger S.N.
        • Smith D.C.
        • McDermott D.F.
        • et al.
        Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
        N Engl J Med. 2012; 366: 2443-2454
        • Hamanishi J.
        • Mandai M.
        • Iwasaki M.
        • Okazaki T.
        • Tanaka Y.
        • Yamaguchi K.
        • et al.
        Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer.
        Proc Natl Acad Sci U S A. 2007; 104: 3360-3365
        • Abiko K.
        • Mandai M.
        • Hamanishi J.
        • Yoshioka Y.
        • Matsumura N.
        • Baba T.
        • et al.
        PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction.
        Clin Cancer Res. 2013; 19: 1363-1374
        • Hamanishi J.
        • Mandai M.
        • Ikeda T.
        • Minami M.
        • Kawaguchi A.
        • Matsumura N.
        • et al.
        Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer.
        J Clin Oncol. 2014; 32
        • Disis M.L.
        Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: a phase Ib, open-label expansion trial.
        J Clin Oncol. 2015; 33 (suppl; abstr 5509)
        • Varga A.
        Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: interim results from a phase Ib study.
        J Clin Oncol. 2015; 33 (suppl; abstr 5510)
        • Peng W.
        • Jiang R.
        • Wu X.
        • Li Z.
        • Sun M.
        • Yu B.
        • et al.
        PDL1, PDL2, and CD8+ TIL expression in ovarian carcinosarcoma.
        J Clin Oncol. 2015; 33
        • Allavena P.
        • Sica A.
        • Solinas G.
        • Porta C.
        • Mantovani A.
        The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages.
        Crit Rev Oncol Hematol. 2008; 66: 1-9
        • Mantovani A.
        • Bottazzi B.
        • Colotta F.
        • Sozzani S.
        • Ruco L.
        The origin and function of tumor-associated macrophages.
        Immunol Today. 1992; 13: 265-270
        • Mantovani A.
        • Allavena P.
        • Sozzani S.
        • Vecchi A.
        • Locati M.
        • Sica A.
        Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors.
        Semin Cancer Biol. 2004; 14: 155-160
        • Pollard J.W.
        Tumour-educated macrophages promote tumour progression and metastasis.
        Nat Rev Cancer. 2004; 4: 71-78
        • Mantovani A.
        • Sozzani S.
        • Locati M.
        • Allavena P.
        • Sica A.
        Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.
        Trends Immunol. 2002; 23: 549-555
        • Mantovani A.
        • Sica A.
        • Locati M.
        Macrophage polarization comes of age.
        Immunity. 2005; 23: 344-346
        • Schioppa T.
        • Uranchimeg B.
        • Saccani A.
        • Biswas S.K.
        • Doni A.
        • Rapisarda A.
        • et al.
        Regulation of the chemokine receptor CXCR4 by hypoxia.
        J Exp Med. 2003; 198: 1391-1402
        • Dave S.S.
        • Wright G.
        • Tan B.
        • Rosenwald A.
        • Gascoyne R.D.
        • Chan W.C.
        • et al.
        Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.
        N Engl J Med. 2004; 351: 2159-2169
        • Cursiefen C.
        • Chen L.
        • Borges L.P.
        • Jackson D.
        • Cao J.
        • Radziejewski C.
        • et al.
        VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment.
        J Clin Invest. 2004; 113: 1040-1050
        • Huang S.
        • Van Arsdall M.
        • Tedjarati S.
        • McCarty M.
        • Wu W.
        • Langley R.
        • et al.
        Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice.
        J Natl Cancer Inst. 2002; 94: 1134-1142
        • Egeblad M.
        • Werb Z.
        New functions for the matrix metalloproteinases in cancer progression.
        Nat Rev Cancer. 2002; 2: 161-174
        • Sica A.
        • Schioppa T.
        • Mantovani A.
        • Allavena P.
        Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy.
        Eur J Cancer. 2006; 42: 717-727
        • Giraudo E.
        • Inoue M.
        • Hanahan D.
        An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.
        J Clin Invest. 2004; 114: 623-633
        • Youn J.
        • Nagaraj S.
        • Collazo M.
        • Gabrilovich D.I.
        Subsets of myeloid-derived suppressor cells in tumor-bearing mice.
        J Immunol. 2008; 181: 5791-5802
        • Gabrilovich D.I.
        • Nagaraj S.
        Myeloid-derived suppressor cells as regulators of the immune system.
        Nat Rev Immunol. 2009; 9: 162-174
        • Mirza N.
        • Fishman M.
        • Fricke I.
        • Dunn M.
        • Neuger A.M.
        • Frost T.J.
        • et al.
        All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients.
        Cancer Res. 2006; 66: 9299-9307
        • Kusmartsev S.
        • Cheng F.
        • Yu B.
        • Nefedova Y.
        • Sotomayor E.
        • Lush R.
        • et al.
        All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination.
        Cancer Res. 2003; 63: 4441-4449
        • Mellman I.
        • Coukos G.
        • Dranoff G.
        Cancer immunotherapy comes of age.
        Nature. 2011; 480: 480-489
        • Curiel T.J.
        • Coukos G.
        • Zou L.
        • Alvarez X.
        • Cheng P.
        • Mottram P.
        • et al.
        Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
        Nat Med. 2004; 10: 942-949
        • Yang L.
        • DeBusk L.M.
        • Fukuda K.
        • Fingleton B.
        • Green-Jarvis B.
        • Shyr Y.
        • et al.
        Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis.
        Cancer Cell. 2004; 6: 409-421
        • Murdoch C.
        • Muthana M.
        • Coffelt S.B.
        • Lewis C.E.
        The role of myeloid cells in the promotion of tumour angiogenesis.
        Nat Rev Cancer. 2008; 8: 618-631
        • Kim R.
        • Emi M.
        • Tanabe K.
        • Arihiro K.
        Tumor-driven evolution of immunosuppressive networks during malignant progression.
        Cancer Res. 2006; 66: 5527-5536
        • Ohm J.E.
        • Carbone D.P.
        VEGF as a mediator of tumor-associated immunodeficiency.
        Immunol Res. 2001; 23: 263-272
        • Ju S.
        • Panka D.J.
        • Cui H.
        • Ettinger R.
        • El-Khatib M.
        • Sherr D.H.
        • et al.
        Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation.
        Nature. 1995; 373: 444-448
        • Strasser A.
        • Jost P.J.
        • Nagata S.
        The many roles of FAS receptor signaling in the immune system.
        Immunity. 2009; 30: 180-192
        • Motz G.T.
        • Santoro S.P.
        • Wang L.
        • Garrabrant T.
        • Lastra R.R.
        • Hagemann I.S.
        • et al.
        Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors.
        Nat Med. 2014; 20: 607-615
        • Yu J.S.
        • Lee P.K.
        • Ehtesam M.
        • Samoto K.
        • Black K.L.
        • Wheeler C.J.
        Intratumoral T cell subset ratios and Fas ligand expression on brain tumor endothelium.
        J Neurooncol. 2003; 64: 55-61
        • Aghajanian C.
        • Blank S.V.
        • Goff B.A.
        • Judson P.L.
        • Teneriello M.G.
        • Husain A.
        • et al.
        OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.
        J Clin Oncol. 2012; 30: 2039-2045