Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.
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DOI：
10.1158/2159-8290.cd-15-1346
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发表时间：
2016-08
期刊：
影响因子：
28.2
通讯作者：
Varner JA
中科院分区：
文献类型：
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作者：
Kaneda MM;Cappello P;Nguyen AV;Ralainirina N;Hardamon CR;Foubert P;Schmid MC;Sun P;Mose E;Bouvet M;Lowy AM;Valasek MA;Sasik R;Novelli F;Hirsch E;Varner JA
胰腺导管腺癌（PDAC）是一种毁灭性的疾病，五年生存率低，但新的免疫治疗方式可能为这种和其他难治性癌症带来希望。在这里，我们报告了PI3Kγ（一种关键的巨噬细胞脂质激酶）的抑制性靶向刺激抗肿瘤免疫应答，从而改善PDAC动物模型的生存率和对标准治疗化疗的反应性。PI3Kγ选择性驱动巨噬细胞中的免疫抑制性转录编程，其抑制适应性免疫应答并促进PDAC中的肿瘤细胞侵袭和结缔组织增生。在携带PDAC的小鼠中阻断PI3Kγ可重新编程肿瘤相关巨噬细胞，以刺激CD8+ T细胞介导的肿瘤抑制，并抑制肿瘤细胞侵袭、转移和结缔组织增生。这些数据表明巨噬细胞PI3Kγ在PDAC进展中发挥的核心作用，并证明PI3Kγ的药理学抑制代表了这种破坏性肿瘤类型的新治疗方式。
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low five-year survival rate, yet new immunotherapeutic modalities may offer hope for this and other intractable cancers. Here we report that inhibitory targeting of PI3Kγ, a key macrophage lipid kinase, stimulates anti-tumor immune responses, leading to improved survival and responsiveness to standard-of-care chemotherapy in animal models of PDAC. PI3Kγ selectively drives immunosuppressive transcriptional programming in macrophages that inhibits adaptive immune responses and promotes tumor cell invasion and desmoplasia in PDAC. Blockade of PI3Kγ in PDAC-bearing mice reprograms tumor-associated macrophages to stimulate CD8+ T cell-mediated tumor suppression and to inhibit tumor cell invasion, metastasis and desmoplasia. These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacological inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.