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

Yang Wang; Yu Zhang; Jing Ouyang; Hanying Yi; Shiyu Wang; Dongbo Liu; Yingying Dai; Kun Song; Wenwu Pei; Ziyang Hong; Ling Chen; Wei Zhang; Zhaoqian Liu; Howard L Mcleod; Yijing He

doi:10.1007/s13402-023-00894-7

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

Cell Oncol (Dordr). 2023 Oct 30. doi: 10.1007/s13402-023-00894-7. Online ahead of print.

Authors

Yang Wang^{1

2

3}, Yu Zhang^{1

2

3}, Jing Ouyang^{1

2

3}, Hanying Yi^{1

2

3}, Shiyu Wang^{1

2

3}, Dongbo Liu^{1

2

3}, Yingying Dai^{1

2

3}, Kun Song⁴, Wenwu Pei⁴, Ziyang Hong⁴, Ling Chen⁴, Wei Zhang^{1

2

3

5}, Zhaoqian Liu^{1

2

3

5}, Howard L Mcleod^{1

6}, Yijing He^{7

8

9

10}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China.
² Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China.
³ Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China.
⁴ Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China.
⁵ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁶ Center for Precision Medicine, Utah Tech University, St George, UT, USA.
⁷ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China. heyijing@csu.edu.cn.
⁸ Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China. heyijing@csu.edu.cn.
⁹ Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China. heyijing@csu.edu.cn.
¹⁰ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. heyijing@csu.edu.cn.

PMID: 37902941
DOI: 10.1007/s13402-023-00894-7

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.

Keywords: Ca2+ channel; IGF1R; Immune; Non-small cell lung cancer; TRPV1; γ-aminobutyric acid.