Study of the immune evasion mechanism in proliferative Verrucous Leukoplakia

• Grant number: 22/14672-0
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2023
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Andreia Bufalino
• Grantee: Andreia Bufalino
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Carlos Eduardo Vergani ; Celso Augusto Lemos Júnior ; Fábio de Abreu Alves ; Omar Kujan ; Paula Aboud Barbugli ; Tuula Anneli Salo nee Viitanen

Abstract

Oral potentially malignant disorders (OPMDs) with epithelial dysplasia are more often associated with malignant transformation to oral squamous cell carcinoma (OSCC). Oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL) are examples of OPMDs that share some clinical (irreversible white plaque) and microscopic (varying degrees of epithelial dysplasia) features but have significantly different behaviour and clinical course. In this context, preliminary results from our research group revealed that the high subepithelial density of CD8+ T lymphocytes and the imbalance of inflammatory cytokines probably play an important role in the pathogenesis of PVL. We also found that the increased expression of calreticulin (CRT) in PVL in relation to OL, may explain the more aggressive behavior of the PVL. Thus, the main hypothesis of this project considers that CD8+ T cells infiltrating the PVL are in a state of exhaustion and that terminally "exhausted" CD8+ T cells lose their CD8 receptors, suggesting the accumulation of double negative T cells in PVL. Furthermore, the increased and persistent expression of CRT, wild or mutant, may be associated with the process of exhaustion of CD8+ T cells in this OPMD. Therefore, an in-depth study of the possible mechanisms of immune evasion is necessary for a better understanding of the involvement of these processes in the pathogenesis of PVL. To test this hypothesis, we propose the following specific objectives: (1) To evaluate the presence of mutations in CRT exon 9 in PVL samples; (2) Evaluate the expression of T cell exhaustion markers and correlate with the expression of CRT through immunohistochemistry in LVP samples; (3 and 4) To evaluate the frequency and subtypes of double negative T cells in PVL, as well as their possible interrelation with the expression of markers associated with T cell exhaustion; and (5) Create a three-dimensional organotypic co-culture system to assess whether elevated CRT expression by dysplastic oral keratinocytes is capable of altering the effector functions of CD8+ T cells in an in vitro model. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARBEIRO, CAMILA DE OLIVEIRA; FERNANDES, DARCY; PALACON, MARIANA PARAVANI; CASTILHO, ROGERIO MORAES; DE ALMEIDA, LUCIANA YAMAMOTO; BUFALINO, ANDREIA. Inflammatory Cells Can Alter the Levels of H3K9ac and gamma H2AX in Dysplastic Cells and Favor Tumor Phenotype. JOURNAL OF PERSONALIZED MEDICINE, v. 13, n. 4, p. 15-pg., 2023-04-01. (18/04954-2, 22/14672-0, 18/22236-0, 17/01798-7, 17/01438-0)