An Immunometabolic Shift Modulates Cytotoxic Lymphocyte Activation During Melanoma Progression in TRPA1 Channel Null Mice

Author(s)

Forni, Maria Fernanda ^{[1, 2]} ; Alberto Dominguez-Amoroch, Omar ^[1] ; Monteiro de Assis, Leonardo Vinicius ^{[3, 4]} ; Kinker, Gabriela Sarti ^[5] ; Moraes, Maria Nathalia ^[6] ; de Lauro Castrucci, Ana Maria ^{[7, 3]} ; Saraiva Camara, Niels Olsen ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Lab Transplantat Immunobiol, Sao Paulo - Brazil

^[2] Yale Univ, Dept Mol Cellular & Dev Biol, Horsley Lab, New Haven, CT - USA

^[3] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Comparat Physiol Pigmentat, Sao Paulo - Brazil

^[4] Univ Lubeck, Ctr Brain Behav & Metab, Inst Neurobiol, Lubeck - Germany

^[5] Int Res Ctr, AC Camargo Canc Ctr, Lab Translat Immunooncol, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Lab Neurobiol, Sao Paulo - Brazil

^[7] Univ Virginia, Dept Biol, Charlottesville, VA - USA

• Document type: Journal article
• Source: FRONTIERS IN ONCOLOGY; v. 11, MAY 10 2021.
• Web of Science Citations: 0

Abstract

Melanoma skin cancer is extremely aggressive with increasing incidence and mortality. Among the emerging therapeutic targets in the treatment of cancer, the family of transient receptor potential channels (TRPs) has been reported as a possible pharmacological target. Specifically, the ankyrin subfamily, representing TRPA1 channels, can act as a pro-inflammatory hub. These channels have already been implicated in the control of intracellular metabolism in several cell models, but little is known about their role in immune cells, and how it could affect tumor progression in a process known as immune surveillance. Here, we investigated the participation of the TRPA1 channel in the immune response against melanoma tumor progression in a mouse model. Using Trpa1 (+/+) and Trpa1 (-/-) animals, we evaluated tumor progression using murine B16-F10 cells and assessed isolated CD8+ T cells for respiratory and cytotoxic functions. Tumor growth was significantly reduced in Trpa1 (-/-) animals. We observed an increase in the frequency of circulating lymphocytes. Using a dataset of CD8+ T cells isolated from metastatic melanoma patients, we found that TRPA1 reduction correlates with several immunological pathways. Naive CD8+ T cells from Trpa1 (+/+) and Trpa1 (-/-) animals showed different mitochondrial respiration and glycolysis profiles. However, under CD3/CD28 costimulatory conditions, the absence of TRPA1 led to an even more extensive metabolic shift, probably linked to a greater in vitro killling ability of Trpa1 (-/-) CD8+ T cells. Therefore, these data demonstrate an unprecedented role of TRPA1 channel in the metabolism control of the immune system cells during carcinogenesis. (AU)

• FAPESP's process: 18/16511-8 - Involvement of the photosensitive and temporal controlling systems in the development, progression, and metastasis of malignant melanoma: an investigation of novel therapeutic targets
• Grantee: Leonardo Vinícius Monteiro de Assis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/14728-0 - Melanopsin as the UVA photoreceptor and its relationship with pigmentation, DNA repair, biological clock and components of the HPA axis: a novel pharmacological target?
• Grantee: Ana Maria de Lauro Castrucci
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/16711-4 - Role of sirtuin 1 in CD4+ T cell activation and differentiation in obese transplanted engrafted animals
• Grantee: Omar Alberto Domínguez Amorocho
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/26651-9 - Glaucoma as a model of temporal information disruption: impact on the metabolism
• Grantee: Maria Nathália de Carvalho Magalhães Moraes Figueira Borges
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/24615-5 - Breaking a paradigm? Melanopsin, a canonical photo-pigment, acting as sensor to entrain the clock in light unexposed organs, and its putative interaction with TRP channels: a trans-disciplinary study involving physiological and pathological aspects
• Grantee: Ana Maria de Lauro Castrucci
• Support Opportunities: Research Projects - Thematic Grants