2. Academic Validation
  3. Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases

Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases

  • J Immunother Cancer. 2024 Dec 4;12(12):e009629. doi: 10.1136/jitc-2024-009629.
Tao Chen # 1 2 3,  Chenxiao Qiao # 4,  Eloy Yinwang # 1 2 3,  Shengdong Wang # 1 2 3,  Xuehuan Wen 5,  Yixuan Feng 6 7,  Xiangang Jin 8,  Shuming Li 9,  Yucheng Xue 1 2 3,  Hao Zhou 1 2 3,  Wenkan Zhang 1 2 3,  Xianchang Zeng 10,  Zenan Wang 1 2 3,  Hangxiang Sun 1 2 3,  Lifeng Jiang 1 2 3,  Hengyuan Li 1 2 3,  Binghao Li 11 2 3,  Zhijian Cai 11 10,  Zhaoming Ye 11 2 3,  Nong Lin 11 2 3
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
  • 2 Orthopaedic Research Institute, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
  • 3 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.
  • 4 Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Featured Laboratory of Respiratory Immunology and Regenerative Medicine in Universities of Shandong, Jinan Clinical Research Center for Respiratory Disease, Jinan, Shandong, People's Republic of China.
  • 5 Department of Oncology, The Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
  • 6 Eye Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
  • 7 Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, Zhejiang, People's Republic of China.
  • 8 Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China.
  • 9 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 10 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 11 Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China linnong@zju.edu.cn yezhaoming@zju.edu.cn caizj@zju.edu.cn libinghao@zju.edu.cn.
  • # Contributed equally.
PMID: 39631847 DOI: 10.1136/jitc-2024-009629
Abstract

Background: Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of TH9 cells is imperative to further unravel their therapeutic potential.

Methods: We adoptively transferred TH1, TH9, and TH17 cells into subcutaneous, in situ, and established lung metastases models of osteosarcoma and triple-negative breast Cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of TH1, TH9, and TH17 cells in the lungs after transfusion. We conducted bulk RNA Sequencing on in vitro differentiated TH9 cells to elucidate the Chemokine Receptor CXCR4, which governs their heightened pulmonary tropism relative to TH1 and TH17 cell counterparts. Using CD4 cre CXCR4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of TH9 cells. We performed mass spectrometry to identify the E3 Ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within TH9 cellular milieu. Ultimately, we analyzed the tumor immune composition after TH9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with TH9 cells.

Results: In this study, we provide evidence that TH9 cells exhibit higher lung tropism than TH1 and TH17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of TH9 cells as ablating CXCR4 in CD4+ T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in TH9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of TH9 cells. Besides, TH9 cells' transfusion significantly improved the immunosuppressed microenvironment. TH9 cells and anti-PD-1 exhibit synergistic effects in tumor control.

Conclusions: Our findings emphasized the innate lung tropism of TH9 cells driven by the activation of TRAF6, which supports the potential of TH9 cells as a promising therapy for established lung metastases.

Keywords

Adoptive cell therapy - ACT; Bone Cancer; Breast Cancer; Immunotherapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z