Cervical cancer is a real worldwide health care issue. High-risk human papillomavirus
      (HR-HPV) chronic infection is a co-factor in the development of the cervical cancer.

      The HR-HPV genome encodes two oncoproteins (E6 and E7) which are required to sustain the
      malignant phenotype of pre-neoplastic lesions and are considered as foreign antigens
      recognized by the immune system, Many studies have suggested that local immunologic escape
      can cause the emergence of HPV-induced cervical cancer Radio-chemotherapy is the gold
      standard treatment for locally advanced cervical cancer, resulting in 2 year-control rates of
      about 70 to 85 %. A better and earlier understanding of the reasons for tumor escape may
      hopefully help to improve these outcomes.

      Both radiation and chemotherapy are myelosuppressive treatments, but new treatment modalities
      such as Intensity-Modulated Radiation Therapy (IMRT) may allow a more rapid hematologic
      recovery. In addition to this immunosuppressive microenvironment, a significant number of
      tumor-infiltrating lymphocytes (TILs) are detected in cervical cancer tissue, highlighting
      interactions between tumor and immune cells.

      Another issue is the fact that cancer cells develop different strategies to bypass the immune
      surveillance, such as a down-regulation of class I human leucocyte antigen (HLA) on tumor
      cells surface.

      Furthermore, there is growing evidence of the importance of immune cells in response to
      cervical cancer treatment. TILs have been correlated with cervical cancer patients' outcome.
      More precisely, the location and type of these immune cells seem to be of great importance
      for the tumor response to treatment.

      Receptors with negative regulatory function have been identified on the surface of those T
      cells, including CTLA4 and PD1 and seem to play a great role in tumor escape to treatment.

      The presence of circulating tumor cells (CTCs) was shown to be correlated with a poor
      patient's prognosis in many cancers. A recent study suggested a potential mechanism of immune
      escape of these CTCs resulting in metastasis spreading.

      The hypothesis of this study is that the frequency of PD1+,CD39+, specific phenotype of the
      non-regulatory CD4+ and CD8+ T cells among TILs is involved with the lack of response to the
      treatment and correlates with an early relapse after the treatment (i.e. patients with a very
      poor prognosis).

      Perspectives:

        -  To set-up another clinical trial with this specific phenotype as the main stratification
           factor. Therefore a more aggressive or a more specific systemic treatment (with or
           without an immunomodulator) could be proposed to those selected patients in the field of
           personalized medicine.

        -  To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for
           immunomonitoring.

        -  To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for
           stratification and monitoring of cancer patients undergoing immune checkpoint
           treatments. This specific subset of CTCs might represent metastatic cells with a high
           potential to escape T cell-mediated lysis and might therefore be the actual targets of
           immunotherapy.