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Cholesterol induction in CD8+ T cell exhaustion in colorectal cancer via the regulation of endoplasmic reticulum-mitochondria contact sites

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Abstract

Background

Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC.

Objective

To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol.

Methods

CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules.

Results

Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells.

Conclusion

High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.

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Abbreviations

CI:

Confidence interval

CTLs:

Cytotoxic T lymphocytes

DCA:

Deoxycholic acid

Dvl:

Dishevelled

ERMCs:

Endoplasmic reticulum-mitochondria contact sites

ERS:

Endoplasmic reticulum stress

HDL-C:

High‐density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

LDLR:

Low-density lipoprotein receptor

LXRs:

Liver X receptors

MACS:

Magnetic cell separation

MMP:

Mitochondrial membrane potential

NHL:

Non-Hodgkin lymphoma

OCR:

Oxygen consumption rate

SREBP2:

Sterol regulatory element-binding protein 2

SQLE:

Squalene epoxidase

TCR:

T-cell receptor

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Funding

This research was supported by Public Welfare Technology Application Research Program of Huzhou (No.2021GY05), Medical and Health Technology Project of Zhejiang Province (No.2022KY1220, No.2021KY343) and Zhejiang Provincial Natural Science Foundation (No. LQ23H160006).

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Authors and Affiliations

  1. Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, 313000, Zhejiang Province, People’s Republic of China

    Han Shuwen, Wu Yinhang, Zhuang Jing, Yan Qiang, Jiang Yizhen, Qi Quan, Jin Yin, Liu Jiang & Yang Xi

  2. Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer of Huzhou, Huzhou, Zhejiang Province, People’s Republic of China

    Han Shuwen, Wu Yinhang, Zhuang Jing, Yan Qiang, Jiang Yizhen, Qi Quan, Jin Yin, Liu Jiang & Yang Xi

  3. Huzhou Central Hospital, Fifth Affiliated Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China

    Han Shuwen, Yan Qiang, Liu Jiang & Yang Xi

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  1. Han Shuwen
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  2. Wu Yinhang
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  3. Zhuang Jing
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  4. Yan Qiang
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  7. Jin Yin
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Contributions

YX and HS conceived of the study. YX and WY wrote the manuscript. YQ and LJ performed the experiments. ZJ drew the figures. QQ, JY and JY analyzed the data. All authors read and approved the paper.

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Correspondence to Yang Xi.

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Ethical approval and consent to participate

Healthy individuals and CRC samples at Huzhou Central Hospital from January 2019 to December 2020 were recruited for this study. This study was approved by the Ethics Committee of Huzhou Central Hospital (No. 20191101-02).

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All patients volunteered to participate in the study and signed a written informed consent.

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262_2023_3555_MOESM1_ESM.tif

Mitochondrial dysfunction in high cholesterol-induced exhausted CD8+ T cells. A, workflow of this part. B, mitochondrial function indices of CD8+ T cells in the normal cholesterol group, high cholesterol group, normal cholesterol colorectal cancer group, and high cholesterol colorectal cancer group: Mitochondrial membrane potential, ATP content, OCR value (cell oxygen respiration O2 consumption rate), ROS relative content, acetyl coenzyme A, NADH/NAD + , and mitochondrial free calcium. C, CD8+ T cells in the high-cholesterol colorectal cancer group were saved by ADP. Comparison of changes in the following mitochondrial functional indicators: mitochondrial membrane potential, ATP content, OCR value (O2 consumption rate in cell aerobic respiration), ROS relative content, acetyl coenzyme A, and NADH/NAD + . D, CD8+ T cells in the high-cholesterol colorectal cancer group were treated with ADP for energy rescue. Flow cytometry was used to detect the expression of the irritant receptor CD69 and inhibitory receptors PD-1, CTLA-4 and TIM- in CD8+ T cells before and after energy rescue. E, the expression levels of the mitophagy-related proteins BINP3, PINK1 and Parkin in CD8+ T cells from mice in the normal cholesterol group, high cholesterol group, normal cholesterol colorectal cancer group and high cholesterol CRC group significantly differed. * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001 (TIF 3171 KB)

Workflow of the study (TIF 4176 KB)

Supplementary file3 (DOCX 23 KB)

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Shuwen, H., Yinhang, W., Jing, Z. et al. Cholesterol induction in CD8+ T cell exhaustion in colorectal cancer via the regulation of endoplasmic reticulum-mitochondria contact sites. Cancer Immunol Immunother 72, 4441–4456 (2023). https://doi.org/10.1007/s00262-023-03555-8

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