Department of General Surgery, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China.
Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China.
Gut. 2023 Nov 24;72(12):2307-2320. doi: 10.1136/gutjnl-2022-329147.
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.
检查点免疫疗法释放了 T 细胞对肿瘤的控制，但被免疫抑制性髓系细胞所抑制。跨膜蛋白 MS4A4A 在肿瘤相关巨噬细胞（TAMs）中选择性高度表达。在这里，我们旨在揭示 MS4A4A TAMs 在调节肿瘤细胞免疫逃逸中的作用，并开发针对 TAMs 的新型治疗策略，以增强免疫检查点抑制剂（ICI）在结直肠癌中的疗效。
使用小鼠皮下肿瘤或原位移植模型评估 MS4A4A 阻断单独或联合 ICI 治疗对肿瘤生长的抑制作用。通过流式细胞术和质谱细胞术评估 MS4A4A 阻断对肿瘤免疫微环境的影响。RNA 测序和 Western blot 分析用于进一步探讨 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选择性地由 TAMs 表达，与癌症患者的不良临床结局相关。体内抑制 MS4A4A 和抗 MS4A4A 单克隆抗体治疗均能抑制肿瘤生长并提高 ICI 治疗效果。MS4A4A 阻断治疗重塑了肿瘤免疫微环境，导致 M2-TAMs 和耗竭 T 细胞浸润减少，效应性 CD8 T 细胞浸润增加。抗 MS4A4A 联合抗程序性细胞死亡蛋白 1（PD-1）治疗在大的、耐药性肿瘤中仍然有效，并且当进一步与放疗联合使用时可以诱导完全消退。在机制上，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 可以增强 ICI 的疗效，代表一种新的抗癌免疫疗法。
