Natural killer cells: role in local tumor growth and metastasis

Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed

Natural killer and dendritic cells crosstalk in vaccination against human papillomavirus

Cervical cancer, the fourth most frequent malignancy in the world, is caused by infection with high-risk human papillomaviruses (HPVs). Recently, we have shown that natural killer (NK) cells are directly activated by virus-like particles (VLPs) formed by the major capsid protein L1 of HPV-16, responsible for more than 50% of uterine cervical cancers. These VLPs are licensed as the first prophylactic vaccine against this cancer. Since NK cells collaborate with dendritic cells (DCs) to induce an immune response against viral infections and tumors, we studied the impact of this crosstalk in the context of HPV vaccination. We have established autologous co-cultures of monocyte-derived DCs with negatively sorted NK cells at a ratio of 1:1. These cells were incubated during 24h with HPV-16 VLPs obtained by self-assembly of L1 proteins produced in baculovirus/insect cell systems and purified on cesium chloride gradient. Lysate of insect cells infected with wild type baculovirus were used as a negative control. NK cells in the presence of VLPs enhanced DC maturation as attested by an upregulation of CD86 and HLA-DR and an increased production of IL-12p70, but not of the immunosuppressive cytokine IL-10. The killing of immature DCs by NK cells was not increased in the presence of VLPs and this could be due to a decreased expression of NKp30L on DCs in the DC-NK-VLP condition.This activation was bi-directional. Indeed, in the presence of VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers such as CD69 and HLA-DR, but not NK cell receptors (NCRs) such as NKp30, NKp44 and NKp46. The function of NK cells was improved as shown by an increase in IFN-gamma; secretion and cytotoxic activity against HPV+ cell line. This crosstalk between NK cells and DCs needed CD40 interaction and IL-12p70 secretion, whereas NKG2D and IFN-gamma; seemed not to be implicated. Our results provide insight into how VLPs interact with innate immune cells and how NK cells and DCs play a role in the immune response induced by this vaccine agent

Origin and immunoescape of uterine cervical cancer

Human papillomavirus associated uterine cervical cancer is an important public health problem since it is classified as the fourth most common cancer in women worldwide with more than 500 000 recorded cases. This review is focused on where and why HPV infection induces cervical cancers and how this virus avoids the host immune response. Immunological therapeutic approaches are also addressed

Regulation of the Immune Response by Innate Lymphocyte and Dendritic Cell Cross Talk

Dendritic cell (DC) is the generic name of different professional antigen presenting cell sub-populations, which are responsible for the initiation of specific immune responses. Recently, DC have been involved in supporting innate immunity by interacting with various innate lymphocytes, such as natural killer (NK), NKT or γδ T (T cells expressing γδ T cell receptor). The functional links between innate lymphocytes and DC have been investigated widely and different studies demonstrated that the cross-talk between innate lymphocytes and DC was found to be multi-directional, involving not only cell-cell contacts but also soluble factors which lead to lymphocyte activation and DC maturation. The final outcome of these cellular interactions may have a dramatic impact on the quality and strength of the down-stream immune responses, mainly in the context of early responses to tumor cells and infectious agents. Interestingly, DC, NK and γδ T cells also share similar functions, such as antigen uptake and presentation, as well as cytotoxic and tumoricidal activity. In addition, NK and NKT cells have the ability to kill DC. This chapter will focus upon the different aspects of the cross-talk between DC and innate lymphocytes and its key role in all the steps of the immune response. These cellular interactions may be particularly critical in situations where immune surveillance requires efficient early innate responses

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPV- associated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-g) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16+ and CD16- NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV–VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions

HPV triggers NK cell cytotoxic activity and cytokine secretion

Background The immune system controls, at least partially, human papillomavirus (HPV) infection and subsequent tumor development as demonstrated by a higher tumor prevalence in immunodeficient patients. Around 90% of HPV-infected women will clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has been performed evaluating the direct interaction between HPV and Natural Killer (NK) cells although these cells play a key role in host resistance to virus and tumor. Methods/Results By immunochemistry, we demonstrated an NK cell infiltration in HPV+ squamous pre-neoplasic lesions. Since HPV cannot grow in vitro, virus-like particles (VLP) were used as a model for studying the NK cell response against the virus. Interestingly, NK cells displayed a higher cytotoxic activity (CD107 and chromium release assays) and cytokine production (TNF-α and IFN-γ) in the presence of HPV-VLP. Uptake of HPV-VLP by dendritic cells (DC) has been shown to induce their activation, therefore, we investigated by flow cytometry and microscopy whether the stimulation of NK cell activity is linked to VLP internalization. We observed a faster entry into these cells compared to DC. Furthermore, virus uptake by NK cells is mediated by macropinocytosis, whereas this entry is dependent on clathrin or caveolin endocytosis pathways in DC. Using NK cell lines expressing or not CD16 and blocking antibody, we demonstrated that CD16 is necessary for HPV-VLP internalization, but also for degranulation and cytokine production. Conclusion Thus, we show for the first time that NK cells interact with HPV and could participate in the immune response against HPV-induced tumors