首页|Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells

Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells

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The enrichment of regulatory T cells(Tregs)in the tumour microenvironment(TME)has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors.C-C motif chemokine receptor 8(CCR8),a marker of activated suppressive Tregs,has a significant impact on the functions of Tregs in the TME.However,the regulatory mechanism of CCR8 in Tregs remains unclear.Here,we revealed that a high level of TNF-α in the colorectal cancer(CRC)microenvironment upregulated CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor.Furthermore,in both anti-programmed cell death protein 1(anti-PD1)-responsive and anti-PD1-unresponsive tumour models,PD1 blockade induced CCR8+ Treg infiltration.In both models,Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy.Finally,we identified that TNFR2+ CCR8+ Tregs but not total Tregs were positively correlated with adverse prognosis in patients with CRC and gastric cancer.Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.

TNFR2CCR8regulatory T cellscolorectal cancer

Yixian Guo、Feng Xie、Xu Liu、Shouyu Ke、Jieqiong Chen、Yi Zhao、Ning Li、Zeyu Wang、Gang Yi、Yanying Shen、Dan Li、Chunchao Zhu、Zizhen Zhang、Gang Zhao、Hong Lu、Bin Li、Wenyi Zhao

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Department of Gastrointestinal Surgery,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Shanghai Institute of Immunology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Department of Immunology and Microbiology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Biotheus Inc.,Zhuhai 519080,China

Department of Pathology,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

GI Division,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of Chinainnovative research team of highlevel local universities in Shanghai

31872740319611330113207087881830051SHSMU-ZDCX20210601

2023

10.1093/jmcb/mjad067

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.(11)
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