Elucidation of immunoregulatory networks associated with response to neoadjuvant therapy in triple negative breast cancer patients

• Grant number: 22/15384-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2023
• End date: April 02, 2026
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Kenneth John Gollob
• Grantee: Ananda Domingues Lopes
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated scholarship(s): 23/07438-3 - Identification of the metabolic profile involved in antitumor T lymphocyte dysfunction and resistance to treatment in triple negative breast cancer, BE.EP.DR

Abstract

Triple negative breast cancer (TNBC) is an aggressive neoplasm characterized by the non-expression of estrogen receptor and progesterone as well as the lack of expression of the HER2 gene. Currently, treatment is based on chemotherapy followed by surgery, where 50% of patients achieve complete recovery, while in the group of patients who do not respond, is noted a tumor progression with a high mortality rate. The immune system plays opposing roles in patients with TNBC, acting in the antitumor defenses, as well as in the disease progression. The presence of infiltrated lymphocytes in the tumor (TILs) is associated with therapeutic response in patients with TNBC. Furthermore, the immune system is shaped by cytokines and chemokines secreted by immune cells in different activation states that are reprogrammed according to the metabolic phenotype. In this project, we aim to characterize the systemic and local immunological profile of patients with CMTN responding or non-responders to neoadjuvant treatment. We will also characterize the metabolic profile and its relationship with the immune response, helping in the therapeutic response or resistance to treatment. Thus, biopsy samples at the time of diagnosis, in addition to peripheral blood samples at pre- and post-treatment times, will be evaluated to understand the development of the antitumor response during neoadjuvant treatment. The cytokines/chemokines will be evaluated in plasma through multiplex assay, the soluble cell profile will be evaluated by flow cytometry and the evaluation of tumor tissue will consist of the evaluation of TILs by H&E staining and multiplex immunofluorescence (IBEX). The influence of the systemic metabolic profile on the modulation of the immune response will be evaluated through the analysis of extracellular flux (EFA - Seahorse)of circulating immune cells from healthy donors in coculture with plasma derived from CMTN patients. This study can support understanding the immune system of patients with TNBC both in the systemic and in the tumor microenvironment, allowing the identification of soluble and cellular biomarkers predictive of response and enabling a more effective therapeutic strategy.