Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer.
Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer.
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DOI：
10.1172/jci.insight.157788
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发表时间：
2022-06-08
期刊：
影响因子：
8
通讯作者：
Moghaddam, Seyed Javad
中科院分区：
文献类型：
--
作者：
Yuan, Bo;Clowers, Michael J.;Velasco, Walter V.;Peng, Stephen;Peng, Qian;Shi, Yewen;Ramos-Castaneda, Marco;Zarghooni, Melody;Yang, Shuanying;Babcock, Rachel L.;Chang, Seon Hee;Heymach, John V.;Zhang, Jianjun;Ostrin, Edwin J.;Watowich, Stephanie S.;Kadara, Humam;Moghaddam, Seyed Javad
K-ras突变肺腺癌(KM-LUAD)与预后不良有关，与促癌炎症密切相关。在Canakinumab抗炎性血栓结果研究中，针对促炎细胞因子IL-1β的人源性单抗Canakinumab显著降低了肺癌的风险。有趣的是，我们在K-RasG12D突变肿瘤小鼠(CC-LR小鼠)的肺中发现了高水平的IL-1β。在这里，我们在6周龄或14周龄CC-LR小鼠的队列中使用抗IL-1β的单抗来阻断IL-1β，以分别探讨其预防和治疗效果。IL-1β阻断可显著降低肺肿瘤负担，这与肺微环境向抗肿瘤表型的重新编程有关，其特征是细胞毒性CD8+T细胞(高表达干扰素-γ和颗粒酶B，但低表达程序性细胞死亡1[PD-1])的渗透增加，同时抑制中性粒细胞和多形核髓系来源的抑制细胞。当查询癌症基因组图谱数据集时，我们发现在KM-LUAD患者中，IL1B的表达与免疫抑制的PMN的渗透及其趋化因子CXCL1和PDCD1的表达呈正相关。我们的数据提供的证据表明，阻断IL-1β可能是高危个体的一种预防策略，也是一种与目前可用的治疗方法相结合的替代治疗方法。
K-ras–mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D–mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti–IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
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Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
影响因子：
--
作者：
Garon EB;Chih-Hsin Yang J;Dubinett SM
通讯作者：
Dubinett SM
影响因子：
16.6
作者：
Caetano MS;Hassane M;Van HT;Bugarin E;Cumpian AM;McDowell CL;Cavazos CG;Zhang H;Deng S;Diao L;Wang J;Evans SE;Behrens C;Wistuba II;Fuqua SAW;Lin H;Stabile LP;Watowich SS;Kadara H;Moghaddam SJ
通讯作者：
Moghaddam SJ
影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
影响因子：
168.9
作者：
Goldstraw, Peter;Ball, David;Shepherd, Frances A.
通讯作者：
Shepherd, Frances A.