MODULATION OF THE TUMOR MICROENVIRONMENT BY AEROBIC PHYSICAL EXERCISE IN LUNG CANCER: DIFFERENCES BETWEEN MALES AND FEMALES

• Grant number: 24/11979-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: August 31, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Cesar Rosa Neto
• Grantee: Lourenço Proença Ruivo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer is one of the leading causes of death globally. Among the types of cancer, lung carcinoma is the most prevalent and deadly. In recent years, the importance of the tumor microenvironment (TME) in the progression and treatment of carcinomas has been widely recognized. The TME refers to the environment in which tumor cells reside, being essential for their survival, growth, and dissemination. This is a dynamic system that includes immune cells, fibroblasts, cytokines, and other components, which can directly or indirectly affect tumor progression. Recently, some studies have sought to understand the impact of physical activity on TME components, with results indicating increased infiltration of CD8+ T lymphocytes and NK cells. An important factor that influences cancer aggressiveness and the TME is the patient's gender. Recent studies have revealed that the TME in women presents higher levels of infiltrated CD4+ T lymphocytes and lower levels of cytokines such as IL-1² and IL-6. However, little is known about how physical exercise specifically modulates the TME in lung cancer, and the differences in exercise response between males and females remain poorly explored. This research project aims to investigate how aerobic physical exercise modulates the TME in lung cancer and to examine the differences in responses between males and females. Male and female C57BL/6 mice will be injected subcutaneously with Lewis lung carcinoma (LLC) cells. The animals will undergo an aerobic physical training protocol for 4 weeks, with sessions lasting 40-60 minutes, 5 times per week, on a treadmill at moderate intensity (approx. 60% of max. speed). After the training period, the mice will be euthanized and the tumors collected for immunophenotyping and evaluation of fibroblasts in the TME by flow cytometry, and quantification of cytokines IL-2, IL-6, IL-10, IFN-³, TNF-±, and IL-15 by ELISA. CD4+ and CD8+ T lymphocytes will be isolated from the tumor and cultured for metabolic analysis of these cells