AXL deficiency in the tumor microenvironment: activation of immune response and resistance to cisplatin

• Grant number: 24/10621-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 28, 2025
• End date: February 27, 2026
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Rossa Junior
• Grantee: Camyla Rodrigues Nascimento
• Supervisor: Keith Lough Kirkwood
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: State University of New York, Buffalo State (SUNY), United States
• Associated to the scholarship: 22/01487-0 - AXL receptor in myeloid cells and the immunosuppressive / efferocytosis loop in oral squamous cell carcinoma, BP.DR

Abstract

AXL is a receptor tyrosine kinase that can be expressed by multiple cell types, however its functions in immune regulation and efferocytosis are best studied in myeloid cells. Dendritic cells rely primarily on AXL for efferocytosis, but its effect in attenuating the pro-inflammatory immune response may also involve macrophages via expression of suppressor of cytokine signaling proteins and immunecheckpoint inhibitors. Collectively, these effects would enhance an immunosuppressive environment with impaired activation of cytotoxic T cells, which may favor tumor progression. We will take advantage of samples obtained from an in vivo orthotopic syngeneic model of oral squamous cell carcinoma using WT and AXL-deficient mice to investigate the relevance of AXL signaling in stromal cells on the expression of selected genes involved in AXL-mediated immunosuppression and cytotoxic T cell activation. RNAscope as the proposed approach allows for multiplexed analyses of gene expression while still retaining information about spatial distribution of the expressed genes in the tumor microenvironment. We will also assess the influence of AXL signaling in stromal cells on the resistance to cytotoxic chemotherapy by two pro-survival candidate routes shown to be relevant in cisplatin resistance: NF-kB activation and MLH1 mispaired base DNA repair mechanism. The results of the proposed experiment will complement and expand the findings of the research projects (PhD stipend and research grant awards) associated with this application.