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Science:一种可激活CD40 蛋白的药物或可治疗胰腺导管腺癌

来源:EurekAlert!中文 2011-03-25 09:47

胰腺导管腺癌,或称PDA,是致死性特别高的一种癌症。但是一项新的研究显示,一种综合性的化疗以及一种可激活CD40 蛋白的药物可在某个病人亚组和小鼠中有效地令肿瘤缩小。 Gregory Beatty及其同事报告了一个临床试验的结果,在该试验中,有少数的罹患无法由手术治愈的PDA病人可得益于这种CD40免疫疗法。研究人员接着分析了在以遗传工程方法制造出来的罹患PDA的小鼠中的治疗结果并发现,该啮齿动物的一个亚组也对治疗有良好的反应。 虽然CD40已知可促进T细胞功能并逆转癌症对免疫系统功能的抑制,但研究人员还是惊讶地发现,由这一CD40 免疫疗法所带来的抗肿瘤效应与巨噬细胞有关。 据研究人员披露,由CD40 所激活的巨噬细胞会迅速地渗入肿瘤之中并促使肿瘤基质的损耗。 鉴于他们的发现,Beatty及其同事提示,治疗诱导的T细胞并非是让免疫系统能够对抗癌细胞所必需的。 他们得出结论:以CD40 激活巨噬细胞可能给人们提供了一种在PDA中快速启动抗肿瘤免疫的手段。 (生物谷Bioon.com)

生物谷推荐原文出处:

Science  DOI: 10.1126/science.1198443

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Gregory L. Beatty1,2,6, Elena G. Chiorean3, Matthew P. Fishman1, Babak Saboury5, Ursina R. Teitelbaum2,6, Weijing Sun2,6, Richard D. Huhn4, Wenru Song4, Dongguang Li4, Leslie L. Sharp4, Drew A. Torigian2,5, Peter J. O’Dwyer2,6, and Robert H. Vonderheide1,2,6,*

Abstract

Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

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