Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
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DOI：
10.1158/2159-8290.cd-15-0827
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发表时间：
2016-03
期刊：
影响因子：
28.2
通讯作者：
Coussens LM
中科院分区：
文献类型：
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作者：
Gunderson AJ;Kaneda MM;Tsujikawa T;Nguyen AV;Affara NI;Ruffell B;Gorjestani S;Liudahl SM;Truitt M;Olson P;Kim G;Hanahan D;Tempero MA;Sheppard B;Irving B;Chang BY;Varner JA;Coussens LM
胰腺导管腺癌（PDAC）是所有实体瘤中五年生存率最差的肿瘤之一，因此迫切需要新的治疗策略。在这里，我们报告说，针对布鲁顿的酪氨酸激酶（BTK），一个关键的B细胞和巨噬细胞激酶，恢复T细胞依赖性抗肿瘤免疫反应，从而抑制PDAC的增长和提高标准的护理化疗（CTX）的反应。我们报道PDAC肿瘤生长依赖于B细胞和FcRγ+肿瘤相关巨噬细胞之间的串扰，导致TH 2型巨噬细胞以磷脂酰肌醇3-激酶（PI 3 K）γ依赖性方式通过BTK活化进行编程。用BTK抑制剂PCI 32765（伊曲替尼）或通过PI 3 K γ抑制处理携带PDAC的小鼠，将巨噬细胞重编程为TH 1表型，其促进CD 8 + T细胞的细胞毒性，并抑制PDAC生长，表明BTK信号传导介导PDAC免疫抑制。这些数据表明，PDAC中BTK的药理学抑制可以重新激活适应性免疫应答，为这种破坏性肿瘤类型提供了一种新的治疗方式。
Pancreas ductal adenocarcinoma (PDAC) has one of the worst five-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here we report that targeting Bruton’s Tyrosine Kinase (BTK), a key B cell and macrophage kinase, restores T cell-dependent anti-tumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy (CTX). We report that PDAC tumor growth depends on crosstalk between B cells and FcRγ+ tumor-associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a phosphatidylinositide 3-kinase (PI3K)γ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a TH1 phenotype that fostered CD8+ T cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacological inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.