The effects of combined inhibition of glutaminolysis and the STAT3 pathway on the tumor microenvironment and the PD-1/PD-L1 axis.

• Grant number: 24/03962-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2024
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ana Paula Lepique
• Grantee: Larissa Fonseca Marques
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The tumor microenvironment (TME) is complex and consists of different cell lineages besides the tumor cells, including endothelial cells, cancer-associated fibroblasts (CAFS), immune cells, as well as soluble components such as cytokines and metabolites, and extracellular matrix components. Reprogramming of energy metabolism is an important hallmark of neoplastic diseases. Compared to normal cells, tumor cells preferentially use the glycolytic pathway. In addition to glycolysis, many tumor cells concomitantly depend on glutaminolysis to obtain energy and macromolecules necessary for cell growth and proliferation. Furthermore, there is evidence that inhibition of glutaminase, in tumor- associated macrophages (TMA), negatively impacts the M2 phenotype. Therefore, glutaminolysis has been a promising therapeutic target for antitumor therapy. STAT3 is a transcription factor that can be activated by cytokines and growth factors, through their JAK family receptors and adapters. Its expression is generally increased in tumor cells, and its chronic activation is related to cell proliferation and immune escape. Studies show that glutamine metabolism is positively related to the STAT3 pathway, and inhibition of glutaminolysis is associated with decreased expression of phosphorylated STAT3. Furthermore, research highlights the positive association of PD-L1, part of the exhaustion axis of immune responses, and STAT3, so that blocking STAT3 tends to alter the PD- 1/PD-L1 pathway, also considered a promising target in antitumor therapy. Our hypothesis is that the blockade of glutaminolysis together with the inhibition of the STAT3 pathway in the TME will simultaneously lead to a reduction in the viability of the malignant cell, modification of the immunological cell phenotype towards a cytotoxic profile and alteration in the PD-1/PD-L1 signaling axis. We intend to work with tumor spheroids derived from cervical cancer cell lines, in coculture with monocytes and initiate protocol optimization to establish organoids (PDOs, patient-derived organoids).