PIM 激酶抑制剂 AZD1208 与 Th1 细胞因子结合使用可增强体外乳腺癌细胞的杀伤力,同时与免疫疗法结合使用还能最大程度地抑制体内肿瘤的生长

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2024-01-08 DOI:10.1016/j.cellimm.2024.104805
Ariel Anwar , Carissa Lepore , Brian J. Czerniecki , Gary K. Koski , Loral E. Showalter
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引用次数: 0

摘要

PIM 激酶在包括乳腺癌在内的多种实体恶性肿瘤中过度表达,被认为能调节增殖、存活和抗药性,因此成为极具吸引力的治疗靶点。由于 PIM 激酶处于多种肿瘤驱动通路的连接点上,PIM 拮抗剂药物正在单独或与其他疗法联合进行测试,以优化治疗效果。因此,我们试图测试药理 PIM 拮抗与 Th1 相关免疫疗法的结合。我们的研究表明,泛PIM拮抗剂AZD1208在体外与Th1细胞因子IFN-γ和TNF-α结合使用时,可在不同表型(HER-2pos/ERneg、HER-2pos/ERpos和三阴性)的人类乳腺癌细胞系中增强代谢抑制、整体细胞死亡和凋亡标志物的表达。有趣的是,AZD1208 能适度抑制受刺激的人类和鼠类 T 淋巴细胞分泌 IFN-γ,这表明该药具有一定的内在免疫抑制活性。然而,在HER-2阳性乳腺癌小鼠模型中测试多重疗法时,与单一治疗组和对照组相比,HER-2肽脉冲DC和AZD1208以及重组IFN-γ加AZD1208的组合能显著抑制肿瘤的生长。这些研究表明,PIM拮抗剂可与某些免疫疗法有效结合,以提高反应性。
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PIM kinase inhibitor AZD1208 in conjunction with Th1 cytokines potentiate death of breast cancer cells in vitro while also maximizing suppression of tumor growth in vivo when combined with immunotherapy

PIM kinases are over-expressed by a number of solid malignancies including breast cancer, and are thought to regulate proliferation, survival, and resistance to treatment, making them attractive therapeutic targets. Because PIM kinases sit at the nexus of multiple oncodriver pathways, PIM antagonist drugs are being tested alone and in conjunction with other therapies to optimize outcomes. We therefore sought to test the combination of pharmacological PIM antagonism and Th1-associated immunotherapy. We show that the pan PIM antagonist, AZD1208, when combined in vitro with Th1 cytokines IFN-γ and TNF-α, potentiates metabolic suppression, overall cell death, and expression of apoptotic markers in human breast cancer cell lines of diverse phenotypes (HER-2pos/ERneg, HER-2pos/ERpos and triple-negative). Interestingly, AZD1208 was shown to moderately inhibit IFN-γ secretion by stimulated T lymphocytes of both human and murine origin, suggesting some inherent immunosuppressive activity of the drug. Nonetheless, when multiplexed therapies were tested in a murine model of HER-2pos breast cancer, combinations of HER-2 peptide-pulsed DCs and AZD1208, as well as recombinant IFN-γ plus AZD1208 significantly suppressed tumor outgrowth compared with single-treatment and control groups. These studies suggest that PIM antagonism may combine productively with certain immunotherapies to improve responsiveness.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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