Cordycepin synergizes with CTLA-4 blockade to remodel the tumor microenvironment for enhanced cancer immunotherapy

Lujun Chen; Xiao Zheng; Hao Huang; Chen Feng; Shaoxian Wu; Rongzhang Chen; Hongwei Jiang; Maoling Yuan; Yuanyuan Fu; Hanjie Ying; Jun Zhou; Jingting Jiang

doi:10.1016/j.intimp.2023.110786

Cordycepin synergizes with CTLA-4 blockade to remodel the tumor microenvironment for enhanced cancer immunotherapy

Int Immunopharmacol. 2023 Nov;124(Pt A):110786. doi: 10.1016/j.intimp.2023.110786. Epub 2023 Aug 21.

Authors

Lujun Chen¹, Xiao Zheng¹, Hao Huang¹, Chen Feng¹, Shaoxian Wu¹, Rongzhang Chen¹, Hongwei Jiang¹, Maoling Yuan¹, Yuanyuan Fu², Hanjie Ying³, Jun Zhou⁴, Jingting Jiang⁵

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China.
² Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Department of Gynecology, Changzhou Traditional Chinese Medicine Hospital, Changzhou, China.
³ College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Jiangsu, Nanjing, China.
⁴ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China. Electronic address: zhouyfan@126.com.
⁵ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Suzhou University, Jiangsu, Changzhou 213003, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu, China. Electronic address: jiangjingting@suda.edu.cn.

PMID: 37611443
DOI: 10.1016/j.intimp.2023.110786

Abstract

The strategy of using immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, leading to remarkable clinical outcomes. However, certain cancer types and patient demographics continue to face unique challenges. As a result, it is vital to investigate combination therapies that involve ICIs to boost therapeutic efficacy. Cordycepin, an adenosine derivative composed of adenine and pentose, holds immense promise for treating inflammation and cancer. Our recent research has demonstrated that the combined treatment of cordycepin and the anti-CD47 antibody significantly curtails tumor growth and extends the lifespan of tumor-bearing mice. In the current study, we showed that the combination of cordycepin and CTLA-4 blockade had a profound impact on suppressing tumor growth. We utilized the MC38 and CT26 tumor models to evaluate the therapeutic effect of cordycepin, CTLA-4 blockade, and their combined approach. Flow cytometry results unveiled that cordycepin, when combined with CTLA-4 blockade, considerably augmented the presence of tumor-infiltrating CD8⁺T cells and diminished the population of Foxp3⁺Tregs within the tumor microenvironment (TME). Additionally, we employed single-cell analysis to examine the TME's reconfiguration upon the combined treatment of anti-CTLA-4 and cordycepin. We observed a significant impact on inhibiting tumor growth and substantially extended survival in tumor-bearing mice. Our data also demonstrated an increased proportion of effector CD8⁺T cells in the combined treatment group compared to all other groups, while exhausted CD8⁺T cells diminished in the combined group compared to the anti-CTLA-4 treatment alone. In conclusion, our findings supported the idea that combining cordycepin and CTLA-4 blockade could modify the effector and exhaustion status of CD8⁺T cells, thereby bolstering CD8⁺T-cell-mediated anti-tumor immunity in the TME. Collectively, our current study successfully established a combination therapeutic strategy utilizing cordycepin and CTLA-4 blockade. This strategy demonstrated a significant synergistic effect against cancer, highlighting its importance in cancer treatment.

Keywords: CTLA-4 blockade; Cancer immunotherapy; Cordycepin; Single-cell RNA sequencing; Tumor microenvironment.

MeSH terms

Animals
CD8-Positive T-Lymphocytes
CTLA-4 Antigen
Humans
Immunotherapy / methods
Mice
Neoplasms* / drug therapy
Tumor Microenvironment*

Substances

cordycepin
CTLA-4 Antigen