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Identification of the metabolic profile involved in antitumor T lymphocyte dysfunction and resistance to treatment in triple negative breast cancer

Grant number: 23/07438-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 21, 2023
Effective date (End): September 20, 2024
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Kenneth John Gollob
Grantee:Ananda Domingues Lopes
Supervisor: Greg Michael Delgoffe
Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Research place: University of Pittsburgh (Pitt), United States  
Associated to the scholarship:22/15384-8 - Elucidation of immunoregulatory networks associated with response to neoadjuvant therapy in triple negative breast cancer patients, BP.DR

Abstract

The triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. The conventional treatment is based on chemotherapy followed by surgery, leading 50% of patients to achieve complete recovery, while patients who do not respond present a high mortality rate. A combined treatment with pembrolizumab (anti-PD-1) in TNBC allow an improvement in clinical outcome. In recent years, advances in immuno-oncology studies enable understanding the immune cell activation mechanisms and their influence on antitumoral response. In TNBC patients, the high levels of tumor infiltrating lymphocytes (TILs) is associated with pathological complete response. The metabolites from tumor microenvironment (TME), such as glutamine, are capable to inhibit antitumoral immune response and can impair the immunotherapy efficacy. The glutamine metabolism is pronounced in TNBC and it is associated with worse prognosis. Our recent findings identified higher levels of tumor infiltrated lymphocytes (TILs) associated with systemic inflammatory cytokines and chemokines in responder TNBC patients. We also evaluate the circulating immune profile in TNBC patients and observed an incapacity of non-responder patients in active or support an antitumoral response, while responder group reveal an adequate activation of immune response. Based on these findings, our hypothesis is that glutamine and other metabolites depravation in TME may impair the development of an effective treatment response. Thus, our goal is investigating the metabolic pathway dynamics in TME over treatment (chemo + anti-PD-1) and the impact on local and systemic immune response and consequent resistance to treatment. The elucidation of these mechanisms can enable the development of more effective therapeutical approaches for TNBC patients. (AU)

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