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An Immunometabolic Shift Modulates Cytotoxic Lymphocyte Activation During Melanoma Progression in TRPA1 Channel Null
Maria Fernanda Forni1, Omar Alberto Domínguez-Amorocho1, Leonardo Vinícius Monteiro de Assis2
1Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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.
Insights
The TRPA1 channel plays a key role in melanoma immune surveillance by regulating immune cell metabolism. Its absence in mice significantly reduced melanoma growth and enhanced CD8+ T cell anti-tumor activity.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Melanoma is an aggressive skin cancer with rising incidence and mortality.
- Transient Receptor Potential (TRP) channels, particularly TRPA1, are emerging as potential therapeutic targets in cancer.
- The role of TRPA1 in immune cell metabolism and its impact on anti-tumor immune surveillance remains largely unknown.
Purpose of the Study:
- To investigate the role of the TRPA1 channel in the immune response against melanoma progression.
- To assess the impact of TRPA1 on CD8+ T cell function and metabolism in the context of melanoma.
Main Methods:
- Utilized Trpa1 wild-type (Trpa1+/+) and knockout (Trpa1-/-) mice with B16-F10 melanoma cells.
- Assessed tumor progression, lymphocyte frequency, and isolated CD8+ T cell respiratory and cytotoxic functions.
- Analyzed CD8+ T cell metabolism and correlated TRPA1 expression with immunological pathways in human metastatic melanoma patients.
Main Results:
- Trpa1-/- mice exhibited significantly reduced tumor growth and increased circulating lymphocytes.
- TRPA1 deficiency altered naive CD8+ T cell mitochondrial respiration and glycolysis.
- Absence of TRPA1 enhanced CD8+ T cell metabolic shift and in vitro killing ability under co-stimulation.
Conclusions:
- TRPA1 channel is a critical regulator of immune cell metabolism during melanoma progression.
- Targeting TRPA1 may represent a novel strategy to enhance anti-tumor immunity and combat melanoma.
