Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC.

[1]  Q. Qian,et al.  Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy , 2019, Frontiers of Medicine.

[2]  A. Skubitz,et al.  Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells. , 2019, Gynecologic oncology.

[3]  O. Lantz,et al.  Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells , 2018, Cell.

[4]  J. Jansen,et al.  Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients , 2018, Oncotarget.

[5]  C. Sessa,et al.  Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  K. Matsuo,et al.  Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series , 2018, Gynecologic oncology reports.

[7]  J. W. Kim,et al.  Major clinical research advances in gynecologic cancer in 2017 , 2018, Journal of gynecologic oncology.

[8]  Dean Anthony Lee,et al.  Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models , 2018, PloS one.

[9]  Jeffrey S. Miller,et al.  Natural Killer Cell-Based Immunotherapy in Gynecologic Malignancy: A Review , 2018, Front. Immunol..

[10]  Paul C. Rogers,et al.  GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity. , 2017, Cancer research.

[11]  A. Schambach,et al.  Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy. , 2017, Human gene therapy.

[12]  S. Gandini,et al.  Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis. , 2017, Gynecologic oncology.

[13]  R. Müller,et al.  Soluble NKG2D ligands in the ovarian cancer microenvironment are associated with an adverse clinical outcome and decreased memory effector T cells independent of NKG2D downregulation , 2017, Oncoimmunology.

[14]  Ludmila V. Danilova,et al.  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade , 2017, Science.

[15]  A. Skubitz,et al.  IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. , 2017, Gynecologic oncology.

[16]  Jeffrey S. Miller,et al.  Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. , 2017, Seminars in immunology.

[17]  S. Paust,et al.  Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients , 2017, International journal of molecular sciences.

[18]  M. Huber,et al.  The Unique Molecular and Cellular Microenvironment of Ovarian Cancer , 2017, Front. Oncol..

[19]  D. Bodurka,et al.  Hormonal Maintenance Therapy for Women With Low-Grade Serous Cancer of the Ovary or Peritoneum. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Jeffrey S. Miller,et al.  Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker , 2016, Oncotarget.

[21]  I. Shih,et al.  Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival? , 2016, Gynecologic oncology.

[22]  M. Aglietta,et al.  Adoptive immunotherapy against ovarian cancer , 2016, Journal of Ovarian Research.

[23]  A. Reuss,et al.  Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. , 2016, Gynecologic oncology.

[24]  N. Matsumura,et al.  PD-1/PD-L1 blockade in cancer treatment: perspectives and issues , 2016, International Journal of Clinical Oncology.

[25]  S. Hauptmann,et al.  The new WHO classification of ovarian, fallopian tube, and primary peritoneal cancer and its clinical implications , 2016, Archives of Gynecology and Obstetrics.

[26]  A. Copik,et al.  Anti-ovarian tumor response of donor peripheral blood mononuclear cells is due to infiltrating cytotoxic NK cells , 2016, Oncotarget.

[27]  I. Sedláková,et al.  Comparative study of various subpopulations of cytotoxic cells in blood and ascites from patients with ovarian carcinoma , 2015, Contemporary oncology.

[28]  S. Kehoe,et al.  Diagnosis of ovarian cancer , 2015, BMJ : British Medical Journal.

[29]  D. Bodurka,et al.  Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum: Results of a Large Single-Institution Registry of a Rare Tumor. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Jacobus Pfisterer,et al.  Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial , 2015, The Lancet. Oncology.

[31]  Jingting Jiang,et al.  B7-H6 expression correlates with cancer progression and patient's survival in human ovarian cancer. , 2015, International journal of clinical and experimental pathology.

[32]  Bert Vogelstein,et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. , 2015, The New England journal of medicine.

[33]  R. Childs,et al.  Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens , 2015, Nature Reviews Drug Discovery.

[34]  D. Kaufman,et al.  Utilizing Chimeric Antigen Receptors to Direct Natural Killer Cell Activity , 2015, Front. Immunol..

[35]  T. Schumacher,et al.  Neoantigens in cancer immunotherapy , 2015, Science.

[36]  G. Tabellini,et al.  B7-H6-mediated downregulation of NKp30 in NK cells contributes to ovarian carcinoma immune escape , 2015, Oncoimmunology.

[37]  Jae-Weon Kim,et al.  Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian and Primary Peritoneal Low-Grade Serous Carcinomas , 2014, International Journal of Gynecologic Cancer.

[38]  W. Mcguire,et al.  Ovarian cancer and antiangiogenic therapy: caveat emptor. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  A. Moretta,et al.  TLR/NCR/KIR: Which One to Use and When? , 2014, Front. Immunol..

[40]  X. Hao,et al.  Maintenance Therapy With Autologous Cytokine-induced Killer Cells in Patients With Advanced Epithelial Ovarian Cancer After First-line Treatment , 2014, Journal of immunotherapy.

[41]  P. D. de Bakker,et al.  HLA-B*13:01 and the dapsone hypersensitivity syndrome. , 2013, The New England journal of medicine.

[42]  A. Whittemore,et al.  Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. , 2013, The Lancet. Oncology.

[43]  A. Sood,et al.  Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma. , 2013, Gynecologic oncology.

[44]  D. Kaufman,et al.  Heterodimeric bispecific single-chain variable-fragment antibodies against EpCAM and CD16 induce effective antibody-dependent cellular cytotoxicity against human carcinoma cells. , 2013, Cancer biotherapy & radiopharmaceuticals.

[45]  S. Kaye,et al.  Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research , 2013, Nature Reviews Cancer.

[46]  Alexia Iasonos,et al.  BRAF Mutation is associated with early stage disease and improved outcome in patients with low‐grade serous ovarian cancer , 2013, Cancer.

[47]  L. Weiner,et al.  Bispecific and Trispecific Killer Cell Engagers Directly Activate Human NK Cells through CD16 Signaling and Induce Cytotoxicity and Cytokine Production , 2012, Molecular Cancer Therapeutics.

[48]  M. Quinn,et al.  Isolation and Characterization of Tumor Cells from the Ascites of Ovarian Cancer Patients: Molecular Phenotype of Chemoresistant Ovarian Tumors , 2012, PloS one.

[49]  G. Mantia-Smaldone,et al.  Immunotherapy in ovarian cancer , 2012, Human vaccines & immunotherapeutics.

[50]  B. Monk,et al.  Incorporation of bevacizumab in the primary treatment of ovarian cancer. , 2011, The New England journal of medicine.

[51]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[52]  Ellen L Goode,et al.  Immunity and immune suppression in human ovarian cancer. , 2011, Immunotherapy.

[53]  P. Peng,et al.  Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. , 2011, Oncology reports.

[54]  M. Caligiuri,et al.  Innate or Adaptive Immunity? The Example of Natural Killer Cells , 2011, Science.

[55]  S. Mok,et al.  BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. , 2010, The American journal of pathology.

[56]  K. Ushijima Treatment for Recurrent Ovarian Cancer—At First Relapse , 2009, Journal of oncology.

[57]  D. Kaufman Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells. , 2009, Blood.

[58]  H. Ljunggren,et al.  Down-regulating Dnam-1 on Nk Cells Cd155 Impair Tumor Targeting by Primary Human Tumor Cells Expressing , 2022 .

[59]  A. Sood,et al.  Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. , 2009, Gynecologic oncology.

[60]  P. Woll,et al.  Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. , 2009, Blood.

[61]  J. Thèze,et al.  A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells1 , 2009, The Journal of Immunology.

[62]  Kiyoko Kato,et al.  Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells. , 2009, Gynecologic oncology.

[63]  D. Chi,et al.  Surgical management of recurrent ovarian cancer. , 2009, Seminars in oncology.

[64]  T. Whiteside,et al.  The Immune Adjuvant Properties of Front-line Carboplatin-Paclitaxel: A Randomized Phase 2 Study of Alternative Schedules of Intravenous Oregovomab Chemoimmunotherapy in Advanced Ovarian Cancer , 2009, Journal of immunotherapy.

[65]  J. Becker,et al.  Macrophage Migration Inhibitory Factor Contributes to the Immune Escape of Ovarian Cancer by Down-Regulating NKG2D1 , 2008, The Journal of Immunology.

[66]  R. Roden,et al.  Antigen‐specific immunotherapy of cervical and ovarian cancer , 2008, Immunological reviews.

[67]  D. Bodurka,et al.  Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. , 2008, Gynecologic oncology.

[68]  G. Han,et al.  Inhibition of human ovarian tumor growth by cytokine-induced killer cells , 2007, Archives of pharmacal research.

[69]  A. Moretta,et al.  Multi-directional cross-regulation of NK cell function during innate immune responses. , 2006, Transplant immunology.

[70]  A. Sood,et al.  Clinical Behavior of Stage II-IV Low-Grade Serous Carcinoma of the Ovary , 2006, Obstetrics and gynecology.

[71]  Wing H Wong,et al.  Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. , 2005, Cancer research.

[72]  A. Moretta,et al.  NK-DC interaction: on the usefulness of auto-aggression. , 2005, Autoimmunity reviews.

[73]  Simon C Watkins,et al.  IL-18–induced CD83+CCR7+ NK helper cells , 2005, The Journal of experimental medicine.

[74]  G. Carta,et al.  Interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced ovarian cancer. , 2005, International journal of oncology.

[75]  Jalid Sehouli,et al.  Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential , 2005, Oncogene.

[76]  J. Seidman,et al.  Benign ovarian serous tumors: a re-evaluation and proposed reclassification of serous "cystadenomas" and "cystadenofibromas". , 2005, Gynecologic oncology.

[77]  R. Ozols Maintenance therapy in advanced ovarian cancer: progression-free survival and clinical benefit. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  R. Kudo,et al.  Comparison of the usefulness between a new universal grading system for epithelial ovarian cancer and the FIGO grading system. , 2003, Gynecologic oncology.

[79]  R. Ozols Ovarian Cancer: American Cancer Society Atlas of Clinical Oncology , 2003 .

[80]  R. Biassoni,et al.  Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[81]  C. Sotiriou,et al.  Molecular determinants of tumor differentiation in papillary serous ovarian carcinoma , 2003, Molecular carcinogenesis.

[82]  Katia Perruccio,et al.  Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatched Hematopoietic Transplants , 2002, Science.

[83]  D. Lubahn,et al.  Natural Killer Cells Express Estrogen Receptor-α and Estrogen Receptor-β and Can Respond to Estrogen Via a Non-Estrogen Receptor-α-Mediated Pathway , 2001 .

[84]  F. Akiyama,et al.  Toward the development of a universal grading system for ovarian epithelial carcinoma , 1998, Cancer.

[85]  A. Favier,et al.  Modulation of natural killer cell functional activity in athymic mice by beta-carotene, oestrone and their association. , 1997, Anticancer research.

[86]  G. Leclercq,et al.  Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells , 1996, The Journal of experimental medicine.

[87]  A. Favier,et al.  Effect of oestrone on the natural killer (NK) cell activity, antioxidant status and tumour growth in athymic mice xenografted with human tumours. , 1996, Anticancer research.

[88]  I. Bérczi,et al.  Modulation of natural killer cell‐mediated cytotoxicity by tamoxifen and estradiol , 1995, Cancer.

[89]  S. Orsulic,et al.  Ovarian Cancer , 1993, British Journal of Cancer.

[90]  K. Bertelsen,et al.  Reproducibility and prognostic value of histologic type and grade in early epithelial ovarian cancer , 1992, International Journal of Gynecologic Cancer.

[91]  I. Weissman,et al.  Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity , 1991, The Journal of experimental medicine.

[92]  John D. Roberts,et al.  Phase I trial of intraperitoneal recombinant interleukin-2/lymphokine-activated killer cells in patients with ovarian cancer. , 1990, Cancer Research.

[93]  W. Urba,et al.  Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  W. Urba,et al.  Intraperitoneal lymphokine-activated killer cell/interleukin-2 therapy in patients with intra-abdominal cancer: immunologic considerations. , 1989, Journal of the National Cancer Institute.

[95]  H. Stalsberg,et al.  Observer variation in histologic classification of malignant and borderline ovarian tumors. , 1988, Human pathology.

[96]  E. Lotzová,et al.  Viral oncolysates in patients with advanced ovarian cancer. , 1988, Gynecologic oncology.

[97]  A. Talerman,et al.  Grading ovarian tumors. Evaluation of decision making by different pathologists. , 1986, Analytical and quantitative cytology and histology.

[98]  R. Freedman Recent immunologic advances affecting the management of ovarian cancer. , 1985, Clinical obstetrics and gynecology.

[99]  R. Bast,et al.  Lymphocyte Cytotoxicity in the Peritoneal Cavity and Blood of Patients With Ovarian Cancer , 1984, Obstetrics and gynecology.

[100]  D. Olive,et al.  Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization , 2017, The Journal of allergy and clinical immunology.

[101]  M. Coleman,et al.  Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study. , 2014, The Lancet. Oncology.

[102]  D. Bowtell,et al.  A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. , 2012, Cancer research.

[103]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[104]  M. Castiglione,et al.  Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[105]  D. Lubahn,et al.  Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway. , 2001, Cellular immunology.

[106]  T. Whiteside,et al.  Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[107]  S. Sone,et al.  Treatment of malignant ascites with allogeneic and autologous lymphokine-activated killer cells. , 1989, Gynecologic oncology.