Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors

Tao Chen; Yucheng Xue; Shengdong Wang; Jinwei Lu; Hao Zhou; Wenkan Zhang; Zhiyi Zhou; Binghao Li; Yong Li; Zenan Wang; Changwei Li; Yinwang Eloy; Hangxiang Sun; Yihang Shen; Mohamed Diaty Diarra; Chang Ge; Xupeng Chai; Haochen Mou; Peng Lin; Xiaohua Yu; Zhaoming Ye

doi:10.1016/j.bioactmat.2022.11.022

Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors

Bioact Mater. 2022 Dec 5:23:508-523. doi: 10.1016/j.bioactmat.2022.11.022. eCollection 2023 May.

Authors

Tao Chen^{1

2

3}, Yucheng Xue^{1

2

3}, Shengdong Wang^{1

2

3}, Jinwei Lu^{1

2

3}, Hao Zhou^{1

2

3}, Wenkan Zhang^{1

2

3}, Zhiyi Zhou⁴, Binghao Li^{1

2

3}, Yong Li⁵, Zenan Wang^{1

2

3}, Changwei Li⁶, Yinwang Eloy^{1

2

3}, Hangxiang Sun^{1

2

3}, Yihang Shen^{1

2

3}, Mohamed Diaty Diarra^{1

2

3}, Chang Ge⁷, Xupeng Chai^{1

2

3}, Haochen Mou^{1

2

3}, Peng Lin^{1

2

3}, Xiaohua Yu^{1

2

3}, Zhaoming Ye^{1

2

3}

Affiliations

¹ Orthopaedic Oncology Services, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
² Orthopaedic Research Institute, Zhejiang University, Hangzhou, 310009, China.
³ Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, China.
⁴ The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310009, China.
⁵ Qingtian People's Hospital, Department of Orthopedics, Lishui, 323900, China.
⁶ Department of Orthopedics, Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 20025, China.
⁷ Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.

Abstract

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy (ACT) against solid tumors. Here, we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors. Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8⁺ T cells, which led to improved antitumor outcomes. Mechanistically, infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation. Overall, we presented a simple, cost-effective, and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.

Keywords: Adoptive cell therapy (ACT); Cell surface engineering; Phage display; Solid tumor; Th9 cell.