Caracterización de los linfocitos infiltrantes de tumor desde la perspectiva del tcr y la presentación antigénica en cáncer de mama

Laburpena

Breast cancer is the most common type of cancer in women and although in the last decades the survival rate has increased, some types of tumors, especially those that do not express hormone receptors such as triple-negative breast cancer, do not have therapeutic alternatives. The study of the immune system may be useful to develop other treatments. Proof of this is that the use of immunotherapy is beneficial in certain types of cancer, although some patients still do not respond. Even in those tumors with a high CD8+ T lymphocytes/Treg ratio –considered a good prognostic marker in breast cancer –some patients do not present a good outcome. On the other hand, it has been reported that the study of the TCR repertoire may have a prognostic and predictive value for the evolution of the disease, as well as for response to treatments. Overall, this indicates that better understanding the anti-tumor response, as well as immune cell types and functions, can help to develop better treatments. The analysis of the TCR repertoire can be useful for its study. However, the great variability of the TCR repertoire and its modification throughout life due to several factors such as age, history of vaccination, infection, or other diseases, as well as the presence of autoimmunity or immunomodulation caused by certain treatments, it hinders its study. The TCR repertoire is highly associated with the HLA haplotype of individuals, as it is configured from its origin in the thymus. At the tumor site, the repertoire will be influenced by the presence of immunogenic antigens capable of activating an immune response and presented as peptides by the HLA molecules. Therefore, the haplotype is a determining factor of the TCR repertoire. The presence of dendritic cells is important for the activation of CD4+ and CD8+ T lymphocytes given their ability to present peptides through HLA II and HLA I molecules, respectively. As the expression of HLA-II molecules is limited to APCs, their presence is especially important for the activation of CD4+ T cells. Other external factors such as the presence of highly frequent viruses in the population, e. g., members of the herpesviridae family, may play a relevant role in shaping the immune response, especially when they are infecting cells from the immune system. The anti-tumor response requires the activation of both CD4+ T lymphocytes, crucial for the initial orchestration and sustainment of the response, and generation of immunological memory, as well as CD8+ T lymphocytes, due to their ability to specifically lyse tumor cells. Considering this, this doctoral thesis has the objective of studying tumor-infiltrating lymphocytes in different types of breast cancer tumors, focused on the CD4+ and CD8+ cell subtypes and with a special interest in the analysis of the TCR repertoire in both subsets. On the other hand, a first proof of concept has been carried out, focused on the study of the repertoire presented by different HLA DR alleles in dendritic cells pulsed with a tumor cell line extract, to determine if there are certain differences in the antigen presentation between different alleles. Finally, tumor-infiltrating EBV+ B lymphocytes in breast cancer, obtained from a xenograft-associated B-cell lymphoma, have been analyzed to study the role of B lymphocytes as antigen-presenting cells and maintain the response of certain lymphocytes T.