Study of the impact of glutaminase 2 on the immune microenvironment and the development of Estrogen-Positive Breast Cancer

• Grant number: 20/11992-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): March 01, 2021
• Effective date (End): December 31, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Ellen Nogueira Lima
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil
• Associated research grant: 21/05726-6 - Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression, AP.TEM

Abstract

Lymphocytes and macrophages infiltrated in the tumor microenvironment reflect the biology of the tumor and impact its prognosis. However, these cells are challenged with a hostile microenvironment and, during the process of tumor development, multiple mechanisms of suppression of the immune system come into play, favoring the growth of the tumor and gaining malignancy. In conjunction with negative immune regulators called immune checkpoints, the function of lymphocytes and macrophages (in addition to other cells of the immune system) is also negatively impacted by a variety of metabolic checkpoints. Recent evidence suggests that deregulation of tumor energy metabolism (with increased consumption of glucose and glutamine) plays a crucial role in inhibiting the anti-tumor immune response and, thus, in progression and metastasis; this is a new and growing area of research. It is known that in an immunosuppressive microenvironment, lymphocytes and macrophages operate at a metabolic disadvantage, since they are subjected to a shortage of crucial carbon sources (glucose and glutamine) and increased inhibitory signals. Recent results from our partially published group showed that patients with breast tumors with high GLS2 expression have a worse prognosis and Breast Cancer cells with higher GLS2 expression proliferate, migrate and invade more. This group of tumors with high GLS2 expression related to worse patient survival is enriched in the luminous and positive subtypes for estrogen receptor positive, which represent the vast majority of breast tumors. In addition, curiously, patients with tumors with high GLS2 expression treated with the hormonal therapy have a worse prognosis than those not treated. These and other preliminary results suggest a role for GLS2 in resistance to these therapies. Preliminary results of in silico analysis indicate that breast tumors with high GLS2 expression present immune environment with low lymphocyte infiltrate, with suppressed Th1 and a high response of alternatively activated pro-tumor macrophages M2. The goal of this project is to understand the role of glutamine metabolism via the glutaminase enzyme GLS2 with the resistance of estrogen positive breast tumor cells to hormonal therapies and with the profile of immune system cells infiltrated in the microenvironment, as well as the tumor progression dependent on this interaction. An in-depth understanding of the metabolic challenges within the microenvironment of this tumor type, and their impacts on the metabolic fitness of immune cells, may contribute to the discovery of new approaches associated with immunotherapy. (AU)