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. Naïve 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.
Highlights
Melanocytes are key players in skin biology since they produce a pigment, melanin, that protects the skin against the deleterious effects of UV radiation and visible light [1, 2]
Through the usage of intact cell metabolic evaluation and flow cytometry, we demonstrated that the lack of TRPA1 in CD8+ lymphocytes (CD8+ T) cells leads to increased respiratory response and glycolysis that culminates with T cell activation and enhanced killing activity
In order to fill this gap, we used a model in which Trpa1+/+ and Trpa1-/- mice were inoculated with B16-F10 melanoma cells to understand CD8+ T activation and tumor progression
Summary
Melanocytes are key players in skin biology since they produce a pigment, melanin, that protects the skin against the deleterious effects of UV radiation and visible light [1, 2]. The uncontrolled and deregulated proliferation of melanocytes may result in cutaneous, mucosal, or uveal melanoma. The interaction of cancer cells with cells and molecules or metabolites in tissues, known as tumor microenvironment, plays an important role in cancer progression [6]. Among these components, immune cells are responsible for the immune surveillance [7,8,9]. Immune cells are responsible for the immune surveillance [7,8,9] They are directly involved in the tumor microenvironment and may favor or halt cancer development [10]. During early stages of cancer, effector immune cells efficiently eliminate immunogenic cancer cells; selected cancer cells that survive, can progress, and evolve to clinically detectable tumors, through several cellular mechanisms that lead to evasion or inactivation of immune cells [10]
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