Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells

Yanyun Du, Qianwen Peng, Du Cheng, Ting Pan, Wanwei Sun, Heping Wang, Xiaojian Ma, Ruirui He, Huazhi Zhang, Zhihui Cui, Xiong Feng, Zhiqiang Liu, Tianxin Zhao, Wenjun Hu, Lei Shen, Wenyang Jiang, Na Gao, Bradley N. Martin, Cun-Jin Zhang, Zhanguo Zhang and Chenhui Wang ()
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Yanyun Du: Huazhong University of Science and Technology
Qianwen Peng: Huazhong University of Science and Technology
Du Cheng: Renmin Hospital of Wuhan University
Ting Pan: Huazhong University of Science and Technology
Wanwei Sun: Huazhong University of Science and Technology
Heping Wang: Huazhong University of Science and Technology
Xiaojian Ma: Huazhong University of Science and Technology
Ruirui He: Huazhong University of Science and Technology
Huazhi Zhang: Huazhong University of Science and Technology
Zhihui Cui: Huazhong University of Science and Technology
Xiong Feng: Huazhong University of Science and Technology
Zhiqiang Liu: Huazhong University of Science and Technology
Tianxin Zhao: Huazhong University of Science and Technology
Wenjun Hu: Huazhong University of Science and Technology
Lei Shen: Renmin Hospital of Wuhan University
Wenyang Jiang: Renmin Hospital of Wuhan University
Na Gao: Huazhong University of Science and Technology
Bradley N. Martin: Brigham and Women’s Hospital, Harvard Medical School
Cun-Jin Zhang: Nanjing University
Zhanguo Zhang: Huazhong University of Science and Technology
Chenhui Wang: Huazhong University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8+ T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy.

Date: 2022
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DOI: 10.1038/s41467-021-27936-8

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