玛嘉烈公主癌症中心Tracy L. McGaha研究组近日取得一项新成果。经过不懈努力，他们揭示了淋巴结巨噬细胞通过诱导免疫调节细胞因子IL-33驱动对癌症治疗的免疫耐受和抵抗。相关论文于2025年3月6日发表在《癌细胞》杂志上。

他们研究了肿瘤引流淋巴结（TDLN）治疗后对死亡肿瘤细胞的免疫反应。负责清除TDLN中肿瘤物质的关键细胞群是髓质内巨噬细胞（MSM）。MSM吞噬肿瘤碎片可诱导细胞因子IL-33，阻断IL-33受体（ST2）或删除MSM中的IL-33可增强治疗效果。从机制上讲，IL-33激活迁移到肿瘤的TDLN中的T调节细胞来抑制CD8⁺ T细胞。联合ST2阻断、靶向激酶抑制剂和抗PD-1免疫治疗可增加CD8⁺ T细胞活性，促进肿瘤消退。重要的是，该课题组在人巨噬细胞中观察到类似的活性，并且IL-33在前哨淋巴结中的表达与黑色素瘤的疾病分期和生存相关。他们的数据确定了一种IL-33依赖性免疫反应，这种免疫反应减弱了治疗诱导的抗肿瘤免疫。

研究人员表示，凋亡细胞具有免疫抑制作用，在癌症治疗中形成屏障。

附：英文原文

Title: Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33

Author: Sara Lamorte, Rene Quevedo, Robbie Jin, Luke Neufeld, Zhe Qi Liu, M. Teresa Ciudad, Sabelo Lukhele, Jessica Bruce, Shreya Mishra, Xin Zhang, Zaid Kamil Saeed, Hal Berman, Dana J. Philpott, Stephen E. Girardin, Shane Harding, David H. Munn, Tak W. Mak, Mikael C.I. Karlsson, David G. Brooks, Tracy L. McGaha

Issue&Volume: 2025-03-06

Abstract: Apoptotic cells are immunosuppressive, creating a barrier in cancer treatment. Thus, we investigated immune responses to dying tumor cells after therapy in the tumor draining lymph node (TDLN). A key population responsible for clearing tumor material in the TDLN was medullary sinus macrophages (MSMs). Tumor debris phagocytosis by MSMs induces the cytokine IL-33, and blocking the IL-33 receptor (ST2) or deletion of Il33 in MSMs enhances therapy responses. Mechanistically, IL-33 activates T regulatory cells in TDLNs that migrate to the tumor to suppress CD8⁺ T cells. Therapeutically combining ST2 blockade, targeted kinase inhibitors, and anti-PD-1 immunotherapy increases CD8⁺ T cell activity promoting tumor regression. Importantly, we observe similar activity in human macrophages, and IL-33 expression in sentinel lymph nodes correlates with disease stage and survival in melanoma. Thus, our data identifies an IL-33-dependent immune response to therapy that attenuates therapy-induced anti-tumor immunity.

DOI: 10.1016/j.ccell.2025.02.017

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00069-8