Single-cell RNA sequencing indicates cordycepin remodels the tumor immune microenvironment to enhance TIGIT blockade's anti-tumor effect in colon cancer

Rongzhang Chen; Chen Feng; Lujun Chen; Xiao Zheng; Weiwei Fang; Shaoxian Wu; Xinran Gao; Can Chen; Jiayi Yang; Yue Wu; Yuanyuan Chen; Panpan Zheng; Nan Hu; Maoling Yuan; Yuanyuan Fu; Hanjie Ying; Jun Zhou; Jingting Jiang

doi:10.1016/j.intimp.2023.111268

Single-cell RNA sequencing indicates cordycepin remodels the tumor immune microenvironment to enhance TIGIT blockade's anti-tumor effect in colon cancer

Int Immunopharmacol. 2024 Jan 5:126:111268. doi: 10.1016/j.intimp.2023.111268. Epub 2023 Nov 21.

Authors

Rongzhang Chen¹, Chen Feng², Lujun Chen³, Xiao Zheng⁴, Weiwei Fang⁵, Shaoxian Wu⁶, Xinran Gao⁷, Can Chen⁸, Jiayi Yang⁹, Yue Wu¹⁰, Yuanyuan Chen¹¹, Panpan Zheng¹², Nan Hu¹³, Maoling Yuan¹⁴, Yuanyuan Fu¹⁵, Hanjie Ying¹⁶, Jun Zhou¹⁷, Jingting Jiang¹⁸

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: CRZ687298@outlook.com.
² Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: fengchen001122@163.com.
³ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: chenlujun@suda.edu.cn.
⁴ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: zhengxiao@suda.edu.cn.
⁵ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: fwwfantasy@163.com.
⁶ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: wushaoxian602@163.com.
⁷ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: gaoxinran1122@163.com.
⁸ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: chencan1085@163.com.
⁹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: yjy981006@163.com.
¹⁰ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: wuyue2021228@163.com.
¹¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: m15250061380@163.com.
¹² Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: zppannn@163.com.
¹³ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: hn_324@163.com.
¹⁴ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: ymlnew@163.com.
¹⁵ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Department of Gynecology, Changzhou Traditional Chinese Medicine Hospital, Changzhou, China. Electronic address: czfy020@njucm.edu.cn.
¹⁶ College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, Jiangsu 211816, China. Electronic address: yinghanjie@njtech.edu.cn.
¹⁷ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: zhouyfan@126.com.
¹⁸ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: jiangjingting@suda.edu.cn.

PMID: 37992442
DOI: 10.1016/j.intimp.2023.111268

Abstract

Both preclinical and clinical studies have extensively proven the effectiveness of TIGIT inhibitors in tumor immunotherapy. However, it has been discovered that the presence of CD226 on tumor-infiltrating lymphocytes is crucial for the effectiveness of both anti-TIGIT therapy alone and when combined with anti-PD-1 therapy for tumors. In our investigation, we observed that cordycepin therapy significantly augmented the expression of the Cd226 gene. As a result, it was hypothesized that cordycepin therapy could enhance the effectiveness of anti-TIGIT therapy. By employing single-cell RNA sequencing analysis of immune cells in the MC38 tumor model, we discovered that cordycepin combined with anti-TIGIT therapy led to a significant increase in the proportion of NK cells within the tumor immune microenvironment. This increased NK cell activity and decreased the expression of inhibitory receptors and exhaustion marker genes. In the combination therapy group, CD8⁺ T cells had lower exhaustion state scores and increased cytotoxicity, indicating a better immune response. The combination therapy group increased DCs in the tumor immune microenvironment and promoted cellular interaction with CD4⁺ T cell and CD8⁺ T cell populations while decreasing Treg cell interactions. In conclusion, cordycepin with anti-TIGIT therapy in colon cancer could reshape the tumor immune microenvironment and have notable anticancer effects.

Keywords: Anti-TIGIT; CD8(+) TILs; Cordycepin; DCs; NK cells; Tumor immune microenvironment.

MeSH terms

CD8-Positive T-Lymphocytes*
Colonic Neoplasms*
Humans
Receptors, Immunologic / metabolism
Sequence Analysis, RNA
Tumor Microenvironment

Substances

cordycepin
Receptors, Immunologic
TIGIT protein, human