15353-j-veluchamy

3 HLA independent killing of cervical tumors by UCB-NK cells | 75 Introduction Persistent infection of the cervical epithelium by high-risk HPV can lead to cervical intraepithelial neoplasia which may progress to invasive cervical cancer, such as squamous cell carcinoma, adenosquamous cell carcinoma or adenocarcinoma 1-3 . Treatment for cervical cancer includes conventional surgery, chemotherapy and/ or radiation. In addition, in advanced (metastatic) disease, targeted therapies are widely explored. Unfortunately, targeted intervention strategies using small molecules, angiogenesis inhibitors and monoclonal antibodies directed against specific tumor antigens and proliferation pathways have had limited success in restricting cervical tumor growth so far 4,5 . In cervical cancer, EGFR is variably expressed in 80% of the tumor tissues 6 . Overexpression of EGFR has been associated with poor prognosis in cervical cancer, making EGFR an obvious candidate for therapeutic targeting 7,8 . However, treatment with cetuximab (CET) (chimeric IgG 1 , anti-EGFR mAb) as monotherapy or CET in combination with chemotherapy was ineffective in patients with cervical cancer, in spite of the apparent absence of activating mutations in the EGFR pathway 9,10 . Immunotherapy of cervical cancer has been clinically explored with limited success. Efforts so far havemostly focused on vaccination approaches against HPV-derived oncogenes (E6 and E7) to trigger an efficacious antitumor T-cell response 11 . Failure to improve clinical outcome may at least in part be due to extensive HLA down-regulation commonly observed in cervical cancer 12-14 . In these cases, NK cell-based therapies may prove more effective than T-cell-based approaches. Indeed, the role of the innate immune response in host defense and viral clearance during (early) infection is well recognized 15 . NK cells are potent in exerting rapid cytotoxicity by releasing cytotoxic granzyme B and perforin in order to lyse virus-infected cells and tumor cell targets. Functional activity of NK cells is regulated by an equilibrium between inhibitory (e.g. CD94/NKG2A) and activating (e.g. CD16, DNAM-1, CD94/NKG2C, CD94/NKG2D) receptors 16,17 . Infiltrating NK cells are observed in low-grade and high-grade cervical intraepithelial neoplasia lesions and to a lesser extent in cervical carcinoma 13,18-21 . In vitro studies have shown that peripheral blood NK cells (PBNK) are able to kill HPV-infected cell lines 19,21,22 . However, NK cells are often dysfunctional and low in number in cervical cancer patients, and thereby unable to mount efficient cytotoxicity against tumors 23,24 . NK cytotoxic function is also counteracted by several cervical tumor escape mechanisms, including low expression of activating NK cell receptor ligands (e.g. MICA/B, ULBPs, Nectin, PVR) and aberrant expression of suppressive non-classical HLA molecules (e.g. HLA-E and -G) by tumor cells 14,19,25-27 . Ex vivo expanded autologous NK cells, adoptively transferred for the treatment of solid tumors, in most studies have yielded disappointing results, underscoring the dire need for the development of more powerful therapeutic approaches to overcome tumor-