Promoting 'good inflammation' and inhibiting 'bad inflammation' in orapharyngeal cancer: role of tumor microenvironment, galanin and GalR2 on the regulation of inhibitory immune checkpoints, cytotoxic activity and efferocytosis

• Grant number: 16/11918-7
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2016 - August 31, 2018
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Morgana Rodrigues Guimarães Stabili
• Grantee: Morgana Rodrigues Guimarães Stabili
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Nisha Jacintha da Silva ; Ricardo Della Coletta

Abstract

Inflammation is proposed as the 7th hallmark of cancer as it is associated with virtually all solid tumors, including oral cancer. Paradoxically, the immune response, which is supposed to detect and clear defective / transformed cells may play roles in both tumor initiation and progression. This has led to the anthropomorphization of the immune response as 'good' or 'bad', depending on the anti- or pro-tumor role of the specific cells or immune-associated molecules. The microenvironment of solid tumors involves a great variety of molecules derived from cancer cells, stromal cells and immune cells and also from the occasional bacterial or viral organisms. This microenvironment is continuously modulating the biology of cancer and immune cells and is the ultimate responsible for tumor progression. Importantly, many of the molecules in the tumor microenvironment, notably cytokines and chemokines, have overlapping or redundant biological roles, which add to the complexity involved in attempting to alter the microenvironment by inhibiting or blocking a single candidate molecule/cytokine. Since the tumor microenvironment (and particularly cancer cell-secreted products) shapes the immune response, an alternative approach is to control immune regulatory checkpoints to promote anti-tumor activity. This can lead to increased killing of cancer cells. Apoptotic cancer cells have to be removed from the microenvironment by efferocytosis, which is a process that can affect the microenvironment and which is also influenced by the microenvironment. The hypothesis is that galanin and GalR2 activity affect immune and cancer cells, favouring 'bad inflammation' (e.g., activation of inhibitory immune checkpoints, decrease of cytotoxic activity, inhibition of M1/Tc1 phenotypes) and inhibiting 'good inflammation' (e.g., activation of stimulatory immune checkpoints, polarization towards Tc1/M1 phenotypes). The goal of these studies is to understand: (1) the effect of galanin and GalR2 activity on the profile of cancer cell-secreted products; and how the activity of stimulatory ('good') and inhibitory ('bad') immune checkpoints is affected by (2) the secreted products from tongue and hypopharynx cancer cells and (3) by the clearance of apoptotic cancer cells by macrophages. These studies will focus on regulatory immune checkpoints and cytokines affecting activation of T cells, NK cells, and macrophages. To test the hypothesis, we propose the following specific aims:1. To verify the effect of galanin and GalR2 activity on the profile of cancer cell-secreted products. 2. To determine the role tumor cell secreted products (with/without galanin stimulation and also after suppression of galanin or GalR2 expression) on the activation of inhibitory (PD1/PD-L1 and CTLA4/B7-1 or B7-2), stimulatory immune checkpoints (GITR/GITRL and CD28/B7-1 or B7-2) and on the activity of CD8+ and NK cells. 3. To investigate the reciprocal influence of tumor cell secreted products (with/without galanin stimulation and also after suppression of galanin or GalR2 expression) on macrophage polarization and efferocytosis. (AU)