Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
Department of Translational Medicine, Division of Cancer Immunology, Lund University, Lund, Sweden.
Int J Cancer. 2020 Jun 15;146(12):3461-3473. doi: 10.1002/ijc.32945. Epub 2020 Mar 20.
Immunotherapeutic modalities are currently revolutionizing cancer treatment. In pancreatic cancer, however, early clinical trials have been disappointing. The optimization of immunotherapeutic strategies requires better understanding of the inflammatory tumor microenvironment. Therefore, the aim of our study was to perform a detailed in situ description of lymphocyte infiltration patterns in resected pancreatic and other periampullary cancers. Multiplexed immunofluorescence imaging was applied to tissue microarrays with tumors from a cohort of 175 patients with resected periampullary adenocarcinoma. A panel of immune cell markers including CD4, CD8α, FoxP3, CD20, CD45RO and pan-cytokeratin was applied to allow for simultaneous spatial analysis of multiple lymphocyte populations. The majority of lymphocyte populations were significantly more abundant in intestinal (I-type) compared to pancreatobiliary (PB-type) tumors. Hierarchical cluster analysis revealed several immune cell signatures of potential clinical relevance. Notably, in the stromal compartment of PB-type tumors, high infiltration of B cells, CD8α CD45RO and single-positive CD4 T cells, but low levels of FoxP3 CD45RO and single-positive CD8α T cells were associated with improved overall survival (OS). The study also defined prognostic relevant topographical patterns of lymphocytic infiltration, in particular proximity of CD8α cells to cancer cells. Moreover, the presence of lymphocytes with potential T-helper capacities (CD4 ) in the nearest vicinity to CD8α cells was associated with a prolonged OS. Our data demonstrate that the composition and clinical impact of immune infiltrates in periampullary adenocarcinoma differ by morphological type as well as localization. Furthermore, spatial in situ analysis identified potential immunological mechanisms of prognostic significance.
免疫治疗方法正在彻底改变癌症治疗。然而，在胰腺癌中，早期临床试验令人失望。免疫治疗策略的优化需要更好地了解炎症肿瘤微环境。因此，我们的研究目的是对切除的胰腺和其他壶腹周围癌症中的淋巴细胞浸润模式进行详细的原位描述。我们应用多重免疫荧光成像技术对来自 175 名接受切除的壶腹周围腺癌患者的组织微阵列进行了分析。该免疫细胞标志物面板包括 CD4、CD8α、FoxP3、CD20、CD45RO 和泛细胞角蛋白，可同时对多种淋巴细胞群进行空间分析。大多数淋巴细胞群在肠型（I 型）肿瘤中明显比胰胆管型（PB 型）肿瘤更丰富。层次聚类分析揭示了几种具有潜在临床意义的免疫细胞特征。值得注意的是，在 PB 型肿瘤的基质区室中，B 细胞、CD8α CD45RO 和单阳性 CD4 T 细胞的高浸润，但 FoxP3 CD45RO 和单阳性 CD8α T 细胞的低水平与总生存期（OS）的改善相关。该研究还定义了淋巴浸润的预后相关拓扑模式，特别是 CD8α 细胞与癌细胞的接近程度。此外，在 CD8α 细胞最近处存在具有潜在辅助性 T 细胞能力的淋巴细胞（CD4）与延长的 OS 相关。我们的数据表明，在胰胆管周围腺癌中，免疫浸润的组成和临床影响因形态类型和定位而异。此外，空间原位分析确定了潜在的具有预后意义的免疫学机制。
