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PIWIL4 as a central regulator of endogenous retroviral elements in Gastric Cancer: implications for immunopathogenesis and immunotherapy?

Grant number: 20/10299-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2021
Effective date (End): June 30, 2023
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Tiago da Silva Medina
Grantee:Glauco Akelinghton Freire Vitiello
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Associated research grant:18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets, AP.JP

Abstract

Endogenous retroviral elements (EREs) are genomic DNA fragments that may retain the capability of replication and reinsertion into the host genome, affecting its structure and integrity. Such are usually deregulated in many human cancers and may trigger the cellular immunogenicity through the activation of innate and adoptive immunity, thus representing promising candidates as immunotherapeutic targets and markers. The regulation of EREs expression occurs at transcriptional and post-transcriptional levels through the piwi-family of RNAs and their associated Argonaut proteins from the PIWIL family (PIWIL1, 2, 3 and 4); among these, PIWIL4 protein is expressed in somatic tissues, whereas other family members are restricted to germline tissues. Therefore, this project seeks to evaluate the role of PIWIL4 as a regulator of EREs in gastric cancer (GC), and the influence of its deregulation on the immune activation in this cancer. For this end, GC cell lines will be comprehensively characterized (methylome, transcriptome, characterization of an antiviral immune response mediated by type I IFNs and identification of neoepitopes) upon PIWIL4 deletion or hyper-expression, analyses in GC patient biopsies will also be performed (gene expression analyses and characterization of the intratumor immune cell composition). In silico analyses performed by our group have indicated that PIWIL4 is aberrantly expressed in GC patients and correlates with overall survival. Besides, PIWIL4 also correlates with the expression of EREs, which in turn correlates with antiviral response genes. Therefore, PIWIL4 may act as a central element on the regulation of EREs in GC and may have implications on anti-tumor immune responses.

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