Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Institute of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Clin Cancer Res. 2020 Jan 1;26(1):220-231. doi: 10.1158/1078-0432.CCR-19-1864. Epub 2019 Oct 4.
Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with locally advanced and borderline resectable pancreatic ductal adenocarcinoma, yet its mechanisms of action on tumor cells and the tumor microenvironment are still unknown. Here, we aimed to characterize the multiple facets of neoTx-induced alterations in the pancreatic cancer microenvironment.
We performed the currently most comprehensive histopathologic analysis of desmoplasia, angiogenesis, neural invasion, and immune cell infiltration at the tumor-host interface of pancreatic cancer after neoTx ( = 37) versus after primary resection ( = 37) through quantitative IHC and double immunofluorescence using automated and software-based quantification algorithms.
We demonstrate that, independently of the applied pretreatment, neoadjuvant regimes are able to reverse the immunosuppressive behavior of malignant cells on pancreatic cancer microenvironment. Here, neoTx-driven selective depletion of regulatory T cells and myeloid-derived suppressor cells was associated with enrichment of antitumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this antitumor immune remodeling correlates to the degree of histopathologic response to neoTx. Survival analysis revealed that the tumor proliferation rate together with the activation of the stroma and the intratumoral infiltration with CD4 T cells and natural killer cells constitute as independent prognostic factors for neoadjuvantly treated pancreatic cancer.
NeoTx is not only cytotoxic but has pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer. Combinational approaches including immunotherapy may unleash long-term and more effective antitumor responses and improve prognosis of pancreatic cancer.
新辅助治疗（neoTx）显著改善了局部晚期和边界可切除的胰腺导管腺癌患者的预后，但它对肿瘤细胞和肿瘤微环境的作用机制仍不清楚。在这里，我们旨在描述 neoTx 诱导的胰腺癌症微环境变化的多个方面。
我们通过定量免疫组化和双免疫荧光，使用自动化和基于软件的定量算法，对 neoTx（n = 37）后与原发性切除（n = 37）后的胰腺癌细胞外基质、血管生成、神经浸润和肿瘤-宿主界面免疫细胞浸润进行了目前最全面的组织病理学分析。
我们证明，无论应用何种预处理，新辅助方案都能够逆转恶性细胞对胰腺癌症微环境的免疫抑制行为。在这里，neoTx 驱动的调节性 T 细胞和髓系来源的抑制性细胞的选择性耗竭与抗肿瘤免疫细胞在肿瘤周围龛中的富集、基质激活减少和神经浸润减少相关。重要的是，这种抗肿瘤免疫重塑的程度与 neoTx 的组织病理学反应程度相关。生存分析显示，肿瘤增殖率以及基质的激活和 CD4 T 细胞和自然杀伤细胞在肿瘤内的浸润，是新辅助治疗胰腺癌的独立预后因素。
neoTx 不仅具有细胞毒性，而且对胰腺癌细胞和非细胞成分具有多种有益的影响。包括免疫疗法在内的联合治疗方法可能会释放出长期和更有效的抗肿瘤反应，并改善胰腺癌的预后。
