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AXL receptor in myeloid cells and the immunosuppressive / efferocytosis loop in oral squamous cell carcinoma

Grant number: 22/01487-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2023
Effective date (End): September 30, 2025
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Carlos Rossa Junior
Grantee:Camyla Rodrigues Nascimento
Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated research grant:20/00394-2 - Head and neck squamous cell carcinoma (HNSCC) invasion and distant metastasis: relevance and crosstalk between GALR2 and efferocytosis in the tumor microenvironment and hematogenic dissemination, AP.TEM

Abstract

The TAM (Tyro3, Axl e Mertk) family of tyrosine kinase receptors and their canonical ligands (Gas6, PROS1) is expressed by multiple cell types and have diverse homeostastic and physiologic roles; however TAM receptors are also considered proto-oncogenes and their increased expression is correlated with occurrence and poor prognosis of various cancers, including oral squamous cell carcinoma (OSCC). Axl has been considered na independent biomarker of poor prognosis in OSCC. This oncogenic association generated a significant interest in the development of pharmacological approaches to inhibit TAM receptors, which have been assessed either as monotherapy or adjuvant therapy in various types of cancer, with a number of phaseI/II clinical trials and one few phase III study. However, there is a relative scarcity of information specifically in OSCC. The main biological roles of TAM receptors are: suppression of pro-inflammatory immune responses and mediation of efferocytosis. OSCC is characteristically immunosuppressive and advanced cases are usually managed by multi-modality treatment including surgical resection and cytotoxic chemo/radiotherapy. In this immunosuppressive TME, massive cell death induced by cytotoxic treatment can trigger efferocytosis, which compounds on the immunosuppression, favoring immunevasion and survival / resistance to treatment. This proposal investigates the relevance of myeloid cell expression of the TAM receptor Axl, especifically, for the progression and resistance to cytotoxic treatment in OSCC. We propose in vitro experiments (3D heterospheroid cultures) and two in vivo models: the chick chorioallantic membrane (CAM) model and a murine orthotopic syngeneic model using transgenic mice with myeloid-specific deficiency of Axl. The main hypothesis is that attenuated activity of Axl in monocytes/macrophages is sufficient to reduce OSCC invasion/progression, by reducing the immunesuppression and activity of efferocytosis, events that combined enhance the anti-tumor immune response by modulating the leukocyte infiltrate and the type of soluble biological ligands in the TME. This proposal is related with the research support award, theme project modality - 2020/00394-2, which will assess the influence of pharmacological modulation of efferocytosis in OSCC progression. Thus, information generated by the proposed studies will complement and expand those of the related theme project on the relevance of efferocytosis for anti-tumor immunity and OSCC progression.

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