美国李-莫菲特癌症中心和研究所Brian Ruffell等研究人员合作发现，坏死样细胞死亡过程中白细胞介素-1α的释放产生髓细胞驱动的免疫抑制并限制抗肿瘤免疫。该项研究成果于2024年11月21日在线发表在《癌细胞》杂志上。

研究人员试图确定免疫激活的机制，但发现坏死性凋亡介导蛋白RIPK3和MLKL在乳腺癌或肺癌的遗传和植入模型中对肿瘤生长是必不可少的。令人惊讶的是，在已建立的乳腺肿瘤中诱导坏死性凋亡会产生骨髓抑制微环境，抑制T细胞功能，促进肿瘤生长，降低生存率。这取决于死亡细胞释放的核警报素白介素-1α (IL-1α)。

关键的是，IL-1α在化疗过程中释放，靶向这种分子降低了肿瘤髓细胞的免疫抑制能力，进而促进了CD8⁺ T细胞的募集和效应功能。在临床前模型中，中和IL-1α可增强单药紫杉醇或联合PD-1阻断治疗的疗效。在一些实体恶性肿瘤中，低IL1A水平与阳性患者预后相关，特别是在接受化疗的患者中。

据介绍，坏死性凋亡可促进抗原特异性免疫反应，提示诱导其是一种治疗癌症的方法。

附：英文原文

Title: Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity

Author: Kay Hnggi, Jie Li, Achintyan Gangadharan, Xiaoxian Liu, Daiana P. Celias, Olabisi Osunmakinde, Aysenur Keske, Joshua Davis, Faiz Ahmad, Auriane Giron, Carmen M. Anadon, Alycia Gardner, David G. DeNardo, Timothy I. Shaw, Amer A. Beg, Xiaoqing Yu, Brian Ruffell

Issue&Volume: 2024-11-21

Abstract: Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generates a myeloid suppressive microenvironment that inhibits T cell function, promotes tumor growth, and reduces survival. This was dependent upon the release of the nuclear alarmin interleukin-1α (IL-1α) by dying cells. Critically, IL-1α release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8+ T cell recruitment and effector function. Neutralizing IL-1α enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low IL1A levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.

DOI: 10.1016/j.ccell.2024.10.014

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00402-1