Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.
Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.
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DOI：
10.1158/2326-6066.cir-14-0027
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发表时间：
2014-07
影响因子：
10.1
通讯作者：
Zheng L
中科院分区：
文献类型：
--
作者：
Lutz ER;Wu AA;Bigelow E;Sharma R;Mo G;Soares K;Solt S;Dorman A;Wamwea A;Yager A;Laheru D;Wolfgang CL;Wang J;Hruban RH;Anders RA;Jaffee EM;Zheng L
胰腺导管腺癌（PDAC）被认为是一种“非免疫原性”肿瘤。单一药剂免疫疗法未能在PDAC和其他“非免疫原性”肿瘤中表现出显著的临床活性，部分原因是复杂的肿瘤微环境（TME）为免疫浸润和功能提供了强大的屏障。我们设计了一项新辅助和辅助临床试验，比较了经辐照的、分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）的同种异体PDAC疫苗（GVAX）作为单一药物或与低剂量环磷酰胺（Cy）联合使用以耗尽调节性T细胞（TME），以研究免疫治疗如何改变TME。对切除的PDAC的检查显示，在疫苗治疗后两周，33/39例患者中形成了疫苗诱导的瘤内三级淋巴聚集体。免疫组织化学分析表明，这些聚集体是适应性免疫的调节结构。微切割聚集体的微阵列分析鉴定了参与调节免疫细胞活化和运输的五种信号通路中的基因表达特征，这些信号通路与改善的疫苗接种后应答相关。这些聚集体中抑制的Treg途径和增强的Th 17途径与存活率提高、接种后间皮素特异性T细胞应答增强和肿瘤内T效应细胞/Treg比率增加相关。这项研究提供了第一个基于免疫的治疗的例子，通过诱导T细胞浸润和三级淋巴结构的发展，在TME转化为“免疫原性”肿瘤的“非免疫原性”肿瘤。GVAX后T细胞浸润和聚集体形成导致免疫抑制调节机制（包括PD-1/PD-L1通路）上调，表明疫苗致敏PDAC患者可能比疫苗初治患者更适合接受免疫检查点和其他免疫调节治疗。
Pancreatic ductal adenocarcinoma (PDAC) is considered a “non-Immunogenic” neoplasm. Single agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other “non-immunogenic” tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neo-adjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as single agent, or in combination with low dose cyclophosphamide (Cy) to deplete regulatory T cells (Tregs), to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33/39 patients two weeks following vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune cell activation and trafficking that were associated with improved post-vaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced post-vaccination mesothelin-specific T-cell responses and increased intratumoral Teffector/Treg ratios. This study provides the first example of immune-based therapy converting a “non-immunogenic” neoplasm into an “immunogenic” neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms including the PD-1/PD-L1 pathway, suggesting that vaccine-primed PDAC patients may be better candidates than vaccine–naïve patients for immune checkpoint and other immunomodulatory therapies.