Exploring the role of neutrophil extracellular traps (NETs) and the SWI/SNF complex in the regulation of the antitumoral immune response

• Grant number: 22/11151-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2022
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: GlaxoSmithKline
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: João Paulo Mesquita Luiz
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Company: Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE)
• Associated research grant: 21/00408-6 - Center for Research in Immuno-Oncology (CRIO), AP.PCPE

Abstract

Extracellular neutrophil traps (NETs) are networks composed of DNA, containing histones and cytotoxic enzymes, which are part of the arsenal to eliminate microorganisms. Initially seen as protective, new evidences demonstrates that NETs can act as a double-edged sword, in addition to microbicidal activity, NETs have deleterious effects in several pathologies. In the tumor microenvironment, tumor-associated neutrophils are activated to release NETs, which play a pro-tumor role by activating pro-survival pathways and protecting tumor cells from the attack of the CD8 T lymphocyte-mediated immune response. We recently demonstrated that activation of the inflammasome, a cytoplasmic complex of innate sensors that recognize patterns associated with damage (DAMPs) and pathogens (PAMPs), via Caspase 11 (CASP11)/Gasdermin D (GSDMD) in neutrophils is a key event for the release of NETs during sepsis. In tumors, it is well known that activation of the inflammasome by DAMPs, such as the release of ATP by tumor cells, results in macrophage activation. However, the activation of this pathway in tumor-associated neutrophils for the production of NETs is not known. SWI/SNF is a chromatin remodeling complex associated with oncogenesis and deregulation of the antitumor immunity cycle. As this complex can regulate about 20-30% of gene expression, mutations in the SWI/SNF genes can affect the cancer patient's response to therapy with checkpoint inhibitors (anti-PD-1/anti-PD-L1) through of the modulation of interferon target genes. Recently, our group demonstrated that DPF3, a member of the SWI/SNF complex, could play an important role in the activation of T CD8+ in the cancer microenvironment. Overexpression of DPF3 increased the growth rate for renal cell lines, while interference of small interfering RNA (siRNA) by the upper DPF3 dysregulated gene, IL23R, reduced the effect of growth on DPF3. Since IL23R interacts with STAT3, we noted increased levels of STAT3 phosphorylation and observed evidence of increased activation of STAT3 signaling by expression analysis. Co-cultures of stimulated tumor cells and peripheral blood mononuclear cells (PBMCs) demonstrated that DPF3 overexpression in tumor cells leads to high PBMC cytotoxicity due to an increased proportion of CD8+ T cells, which DPF3 could influence the response immunotherapy through an epigenetic mechanism, using the genes of the SWI/SNF complex. (AU)