Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer
Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer
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DOI：
10.1158/0008-5472.can-17-2415
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发表时间：
2018-01-15
期刊：
影响因子：
11.2
通讯作者：
Kuehnel, Florian
中科院分区：
文献类型：
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作者：
Brooks, Jennifer;Fleischmann-Mundt, Bettina;Kuehnel, Florian
胰腺导管腺癌(PDAC)是一种高度致命性和播散性的癌症，对治疗耐药，包括检查点免疫治疗，早期肿瘤切除和(NEO)辅助化疗未能改善不良预后。在可切除PDAC转基因小鼠模型中，除了吉西他滨化疗外，我们还研究了T细胞和自然杀伤(NK)细胞的协同激活以防止肿瘤复发。只有使用PD-1拮抗剂的新辅助治疗才能有效地支持化疗，抑制局部肿瘤复发，并提高NK和T细胞的存活率。肿瘤中CD103(+)CD(+)T细胞和针对新表位LAMA4-G1254V的新抗原特异性CD8 T细胞的浸润增加，证实了局部T细胞的激活。为了以一种互补的方法有效地预防远处转移，我们阻断了NK细胞检查点CD96，这是一种结合CD155的抑制性NK细胞受体，在原发PDAC和人类患者的转移中大量表达。在吉西他滨治疗的小鼠中，新佐剂PD-1阻断后辅助性抑制CD96显著防止了PDAC的复发，从而允许长期生存。综上所述，我们的结果表明，在积极生长的PDAC转基因小鼠模型中，天然免疫和获得性免疫的协调激活可以有效地降低手术后肿瘤复发的风险，促进这种致命疾病的长期缓解。意义：协同的新辅助和佐剂免疫疗法降低了小鼠PDAC切除后疾病复发的风险，这表明这一概念适用于未来的临床试验。(C)2017年AACR。
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo) adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103(+)CD(+) T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.Significance: Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials. (C) 2017 AACR.