Exploring the role of neutrophil extracellular traps (NETs) and the SWI/SNF complex in regulating the anti-tumor immune response.

• Grant number: 25/11510-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: June 30, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Malena Martínez Pérez
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

An updated definition of cancer refers to a large group of diseases characterized by the uncontrolled growth of transformed cells subject to evolution by natural selection. In this sense, studies related to the role of neutrophil extracellular traps (NETs) in the tumor microenvironment have been controversial. NETs are network-like structures composed of DNA-histone complexes and cytoplasmic enzymes of activated neutrophils that play an important role in the body's defense mechanisms to eliminate microorganisms. Initially seen as protective, new evidence shows that NETs may have a dual role; in addition to their microbicidal activity, they have deleterious effects in several pathologies. In the tumor microenvironment, neutrophils release NETs, ¿¿which also play a controversial role, and may have cytotoxic effects on tumor cells, or a pro-tumor role by activating pro-survival pathways, involvement in cancer immunoediting, progression, metastatic dissemination, and protecting tumor cells from attack by the immune response mediated by CD8 T lymphocytes. Several mechanisms have been described in cancer as responsible for NETosis in neutrophils, among them the production of reactive oxygen species (ROS), activating the migration to the nucleus of both PAD-4 and neutrophil elastase, both enzymes that induce histone modifications, with consequent chromatin decondensation, initial events in the formation of NETs. Subsequently, the release of NETs depends on the activation of gasdermin D (GSDMD) with the formation of pores in the cell membranes through which NETs are released. We recently demonstrated that activation of the inflammasome, a cytoplasmic complex of innate sensors that recognize damage-associated patterns (DAMPs) and pathogens (PAMPs), via activation of Caspase 1 or 11 (CASP1; 11), which participate in the activation of GSDMD, is a key event for the release of NETs during sepsis. In tumors, it is already known that activation of the inflammasome by DAMPs and the release of ATP by tumor cells results in the activation of macrophages. However, the activation of this pathway, as well as the role of elastase release in tumor-associated neutrophils in inducing or not the production of NETs, ¿¿is still unknown. On the other hand, it is already described in the literature that approximately 25% of tumors have mutations in one or more genes of the SWI/SNF complex. SWI/SNF is a chromatin remodeling complex associated with oncogenesis and dysregulation of the antitumor immunity cycle. Since changes in chromatin are a central event for the release of NET by neutrophils, the mechanism by which aberrations in the genes of this complex could enhance or inhibit the formation of NET in the tumor microenvironment is still poorly studied. Knowledge of the mechanisms of NET release in different types of cancer could influence the immunotherapeutic response, bringing more effective and humanized treatments to patients.