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.

Virus‐like particles (VLPs) of human papillomavirus (HPV) are used as a vaccine against HPV‐induced cancer, and recently we have shown that these VLPs are able to activate natural killer (NK) cells. 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. NK cells in the presence of HPV‐VLPs enhanced DC‐maturation as shown by an upregulation of CD86 and HLA‐DR and an increased production of IL‐12p70, but not of the immunosuppressive cytokine IL‐10. This activation was bidirectional. Indeed, in the presence of HPV‐VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLA‐DR). The function of NK cells was also improved as shown by an increase in IFN‐γ secretion and cytotoxic activity against an HPV+ cell line. This crosstalk between NK cells and DCs needed CD40 interaction and IL‐12p70 secretion, whereas NKG2D was not 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.

High-risk human papillomavirus infection is the etiological agent of cervical cancer, the third cause of cancer-associated death in women worldwide. Gamma delta T cells (γδ T cells) represent a small population of T cells expressing a T cell receptor (TCR) composed of gamma and delta chains. Their role in the context of HPV-induced lesions was not investigated yet, but we previously showed an infiltration of γδ T cells in this cancer, suggesting a relationship between HPV-induced lesions and γδ T cells. The goal of this project is to study the role of γδ T cells in the immune response against HPV-induced tumours. In order to study the role of γδ T cells in HPV-induced lesions, we have established a mouse model by crossing transgenic mice expressing HPV16 oncogenic genes, which develop spontaneous skin lesions, with γδ T cell-deficient mice. Surprisingly, depletion of γδ T cells significantly delays development of HPVinduced lesions. In parallel, we observed by immunohistochemistry an increase of leukocyte infiltration in HPV-induced lesions in absence of γδ T cells. Then, we evaluated by flow cytometry the proportions of immune cell populations present in the mouse skin and we found a larger proportion of CD4+ T cells in HPV and HPV γδ T cell-deficient mice compared to normal mice. Since γδ T cells could induce angiogenesis when infiltrating tumors, we measured blood vessels density in mice skin sections and we observed a significantly increase of blood vessels density in HPV mice compared to HPV γδ T cells-deficient mice. Our results suggest that γδ T cells could promote cancer progression in the context of HPV-induced lesions. We will further characterise these cells to understand in which cellular and molecular mechanisms they are involved.

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.

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‐α and IFN‐γ) 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.

Persistent infection with oncogenic human papillomavirus (HPV) genotypes is a necessary cause of anogenital cancer and HPV infections account for more than 50% of infectionlinked cancers in women worldwide. The immune system controls, at least partially, viral infection and subsequent tumor development. 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 NK cells although these cells play a key role in host resistance to virus and tumor. 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 and cytokine production (TNF-α and IFN-γ) in the presence of VLP. Uptake of VLP by dendritic cells (DC) has been shown to induce their activation, therefore, we investigated 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 of 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. Moreover, we observed a phosphorylation of Erk and p38, two MAP Kinases (MAPK) involved in NK cell cytotoxic activity and with specific inhibitors, we demonstrated that these MAPK are implicated in NK cell degranulation against VLP.

The cover shows a modified electron microscopic image of HPV16-virus-like particle (HPV16-VLP)-internalization by NK cells. The colour added to the cover image is purely for aesthetic purposes and has no biological significance. The original, unmodified image is from Renoux et al. (pp. 3240–3252) in which the authors demonstrate that HPV16-VLPs are taken up by NK cells by macropinocytosis. CD16 is shown to play a central role in the NK cell response to HPV16, being shown to be required for viral uptake, and for granzyme and cytokine release.

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 gamma delta T (T cells expressing gamma delta 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 gamma delta 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.