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Cervical cancer is the second most common cancer in women worldwide.(1) It is caused by a persistent infection with high-risk human papilloma virus (HPV) types, in particular, HPV16 and HPV18. (2;3) These high-risk HPV infections account for approximately two thirds of all cervical carcinomas. (4) Cervical lesions can progress via cervical intraepithelial neoplasia (CIN) to cervical cancer.(2) The HPV genome encodes two well-known tumor-specific oncoproteins, E6 and E7. These oncoproteins are expressed in both premalignant- and malignant cervical cells.(1;5)
The most frequent site of local spread of cervical carcinoma is the parametrium. Metastatic spread is mainly lymphatic. One of the most important prognostic factors in early stage cervical carcinoma is the presence of metastatic carcinoma in the pelvic lymph nodes.(6) Lymph node spread is detected in about 27% of early stages of cervical cancer, with the pelvic nodes as the most common location for metastases.(7;8)
Tumor draining lymph nodes are the location in which adaptive, tumor-specific immune responses are initiated.(9) Solid tumors are generally surrounded or infiltrated by leukocytes, including T and B lymphocytes, natural killer (NK) cells and macrophages, suggesting a host immune response to the tumor.(10;11)
Dendritic cells (DCs) play a very important role in tumor immunity. (3;12) DCs are bone marrow-derived antigen-presenting cells that are crucial for the initiation of T-cellââ‚¬"mediated immunity. (13)
Tumor-infiltrating dendritic cells can uptake tumor antigens with class II human major histocompatibility complex (MHC) molecules. In lymph nodes, these tumor antigen-loaded dendritic cells can infer tumor-specific CD4+ T cells that can produce lymphokines that amplify the cytotoxic activity of CD8+ T cells. (9;14) These tumor-specific CD8+ and CD4+ T cells can recognize the E6 and E7 tumor antigens and destroy tumor cells in vitro. (1)
Langerhans cells belong to the lineage of dendritic cells and thus, they play an important role in local immune defence as antigen-presenting cells through specific cooperation with T lymphocytes. (15) They take up and transport tumor-associated antigens to tumor draining lymph nodes. (13) The increase in the number of Langerhans cells is significantly associated with increase in the number of CD4+, NK and B cells. The number of CD4+ cells is also significantly associated with the number of CD8+ cells. These associations may suggest that a Langerhans cell is the effector cell in primary T lymphocyte response in cervical carcinomas. (15)
Some studies suggest that high numbers of tumor-infiltrating lymphocytes are associated with decreased overall survival of patients, on the other hand, some studies report an increase in survival. This suggests that the clinical outcome may be dependent on the type of immune cells present and not on the total number of immune cells. (2)
In some cancers CD3+CD8+ T cells are associated with a better prognosis. The infiltration by CD3+CD4+ T cells or a subpopulation of CD4+ T cells, also known as regulatory T cells (tregs), were reported to erase the positive effect of CD8+ T cells. Forkhead box protein-3 (Foxp3) is required for the detection of Tregs. (16)
Sheu et al. demonstrated that in patients with lymph node metastases, a decreased median percentage of tumor-infiltrating CD4+ T cells, but not CD8+ T cells, were seen. The CD4/CD8 ratio was significantly lower because of a decline in the amount of infiltrating CD4+ T cells. Inadequate activation of tumor specific CD4+ T-helper cells can result in failure of the antitumor immune response by CD8+ T cells. (14) Increased survival is seen in high ratios between activated CD8+ T cells and the other immune cell types. (4)
It is obvious that the immune system plays an important role in cervical cancer. But the precise immune status of different lymphocytes in lymph nodes remain unclear. Metastatic lymph node removal would not just eradicate a metastasis but also immune cells. (16)
Rapid tumor growth and lymph node metastasis may occur because of immune-mediated recognition and destruction by the tumor.(17) Class I MHC genes encode classical Ia human leukocyte (HLA-A, HLA-B and HLA-C), and non-classical Ib (HLA-E, HLA-F and HLA-G) antigens. Certain tumor inducing viruses, including HPV, may down regulate HLA class Ia molecules on antigen presenting cells by producing peptides homologous to HLA class Ia. (18) Loss of surface-expressed HLA class Ia molecules make tumor cells evading recognition and lysis by cytotoxic T-lymphocytes. (17) On the other hand, virus induced tumors can up regulate HLA class Ib molecules, allowing the virus to escape from NK cells of the human body. (18)
An other mechanism the tumor can use to avoid the human immune system is the expression of indoleamine 2, 3-dioxygenase (IDO). IDO is a tryptophan-catabolizing enzyme which seems to block the proliferation of alloreactive T lymphocytes and NK cells. IDO causes the arrest of T lymphocytes and NK cells in the G1 phase of the cell cycle. Hereby, the immune response is suppressed by blocking the killer function of T cells and NK cells. (19;20)
In summary, previously we have shown that cervical cancer cells can avoid the immune system by downregulating classical HLA class I expression, resulting in tumor outgrowth and detrimental for patient survival. The composition of the immune cell infiltrate at the tumour site was also found to be crucial to survival. In addition, various factors produced by the neoplastic cells, such as IDO and arginase, can lead to immune cell anergy facilitating immune escape. As lymph node positivity is the clinical parameter that is most detrimental for survival, the study of the immune escape mechanisms employed by metastasising cervical cancer cells and the immune cell composition of draining lymph nodes will give us crucial information as to what intervention points can be used for targeted immunotherapy.