Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.
Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.
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DOI：
10.1136/gutjnl-2022-329147
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发表时间：
2023-11-24
期刊：
影响因子：
24.5
通讯作者：
Deng, Haijun
中科院分区：
文献类型：
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作者：
Li, Yongsheng;Shen, Zhiyong;Chai, Zhen;Zhan, Yizhi;Zhang, Yaowei;Liu, Zhengyu;Liu, Yuechen;Li, Zhenkang;Lin, Mingdao;Zhang, Zhanqiao;Liu, Wei;Guan, Shenyuan;Zhang, Jinchao;Qian, Junying;Ding, Yi;Li, Guoxin;Fang, Yuan;Deng, Haijun
检查点免疫疗法释放t细胞对肿瘤的控制，但被免疫抑制性骨髓细胞抑制。跨膜蛋白MS4A4A在肿瘤相关巨噬细胞（tam）中选择性高表达。在此，我们旨在揭示MS4A4A+ tam在调节肿瘤细胞免疫逃逸中的作用，并开发针对tam的新治疗策略，以提高免疫检查点抑制剂（ICI）在结直肠癌中的疗效。采用小鼠皮下肿瘤或原位移植模型评估单独或联合使用MS4A4A阻断剂对肿瘤生长的抑制作用。采用流式细胞术和质粒细胞术观察阻断MS4A4A对肿瘤免疫微环境的影响。通过RNA测序和western blot分析进一步探讨MS4A4A促进巨噬细胞M2极化的分子机制。MS4A4A在不同类型的肿瘤中由tam选择性表达，并与癌症患者的不良临床结果相关。体内抑制MS4A4A和抗MS4A4A单克隆抗体治疗均可抑制肿瘤生长，提高ICI治疗效果。MS4A4A阻断治疗重塑肿瘤免疫微环境，导致m2 - tam和耗竭T细胞的浸润减少，效应CD8+ T细胞的浸润增加。抗ms4a4a +抗程序性细胞死亡蛋白1 （PD-1）治疗在大的、治疗耐药的肿瘤中仍然有效，并且在进一步联合放疗时可以诱导完全消退。机制上，MS4A4A通过激活PI3K/AKT通路和JAK/STAT6通路促进巨噬细胞M2极化。靶向MS4A4A可提高ICI的疗效，是一种新的抗癌免疫治疗方法。
Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.
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影响因子：
120.1
作者：
Kim, Tae Kon;Vandsemb, Esten N.;Chen, Lieping
通讯作者：
Chen, Lieping
单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
17.1
作者：
Gurbatri CR;Lia I;Vincent R;Coker C;Castro S;Treuting PM;Hinchliffe TE;Arpaia N;Danino T
通讯作者：
Danino T