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TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response

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Abstract

Purpose

TRPV1 is a nonselective Ca2+ channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly.

Method

The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry.

Results

In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca2+-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4+ T cells, CD8+ T cells, GZMB+CD8+ T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC.

Conclusion

Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.

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Data Availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 82173906); the key project of Ministry of Science and Technology, China (2022YFC2010004); Chinese National Major Project for New Drug Innovation. (No. 2019ZX09201-002-006); the key project of Health Commission of Hunan Province (No.202113010141); Natural Science Foundation of Hunan Province, China (No.2021JJ31063 and No.2021JJ31044). Fundamental Research Funds for the Central Universities of Central South University (No.198101066 and No.208111176).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China

    Yang Wang, Yu Zhang, Jing Ouyang, Hanying Yi, Shiyu Wang, Dongbo Liu, Yingying Dai, Wei Zhang, Zhaoqian Liu, Howard L. Mcleod & Yijing He

  2. Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China

    Kun Song, Wenwu Pei, Ziyang Hong & Ling Chen

  3. Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China

    Yang Wang, Yu Zhang, Jing Ouyang, Hanying Yi, Shiyu Wang, Dongbo Liu, Yingying Dai, Wei Zhang, Zhaoqian Liu & Yijing He

  4. Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China

    Yang Wang, Yu Zhang, Jing Ouyang, Hanying Yi, Shiyu Wang, Dongbo Liu, Yingying Dai, Wei Zhang, Zhaoqian Liu & Yijing He

  5. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Wei Zhang, Zhaoqian Liu & Yijing He

  6. Center for Precision Medicine, Utah Tech University, St George, UT, USA

    Howard L. Mcleod

Authors
  1. Yang Wang
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Contributions

Yijing He designed and guided the experiments; Yang Wang conducted the experiments, wrote the manuscript, and analyzed the data; Yu Zhang, Jing Ouyang, Hanying Yi, and Shiyu Wang contributed to the cell experiments; Dongbo Liu, Yingying Dai Ziyang Hong and Wenwu Pei helped to use equipment and instruments. Yijing He, Kun Song, Ling Chen, Wei Zhang, Zhaoqian Liu and Howard L. Mcleod supervised and reviewed the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Yijing He.

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The animal study was reviewed and approved by the Ethics Committee of the Xiangya Hospital, Central South University, Changsha, China.

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Wang, Y., Zhang, Y., Ouyang, J. et al. TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response. Cell Oncol. (2023). https://doi.org/10.1007/s13402-023-00894-7

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