PITPNC1 Suppress CD8 <sup>+</sup> T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155

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Abstract

Background

Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance.

Methods

To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8 ⁺ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8 ⁺ T cell immune function.

Results

Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8 ⁺ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8 ⁺ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models.

Conclusions

PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8 ⁺ T cell immune function, and promotes radioresistance in rectal cancer.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-024-04931-3.

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Author and article information

Contributors

Chunhui Cui: drcuich@163.com

Yujing Tan: tanyujing-1981@163.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 30 January 2024

Publication date PMC-release: 30 January 2024

Publication date Collection: 2024

Volume: 22

Electronic Location Identifier: 117

Affiliations

[1 ]GRID grid.417404.2, ISNI 0000 0004 1771 3058, Department of General Surgery, , Zhujiang Hospital, Southern Medical University, ; Guangzhou, China

[2 ]GRID grid.417404.2, ISNI 0000 0004 1771 3058, Department of Radiation Oncology, , Zhujiang Hospital, Southern Medical University, ; Guangzhou, China

[3 ]GRID grid.416466.7, ISNI 0000 0004 1757 959X, Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, , Nanfang Hospital, Southern Medical University, ; Guangzhou, China

Article

Publisher ID: 4931

DOI: 10.1186/s12967-024-04931-3

PMC ID: 10826121

PubMed ID: 38291470

SO-VID: 90764c18-6d2f-4c69-a382-a04e3652bd93

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 September 2023

Date accepted : 25 January 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82003209

Award Recipient : Yujing Tan

Funded by: Science and Technology Program of Guangzhou

Award ID: 202102080072

Award Recipient : Yujing Tan

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: pitpnc1,cd8+ t cell,immunosuppression,rectal cancer,radioresistance

Data availability:

ScienceOpen disciplines: Medicine

Keywords: pitpnc1, cd8+ t cell, immunosuppression, rectal cancer, radioresistance