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+ CD45ROhigh 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.

中文翻译：

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壶腹周围和胰腺腺癌中淋巴细胞浸润的定量，定性和空间分析。

免疫治疗方法目前正在彻底改变癌症治疗。然而，在胰腺癌中，早期的临床试验令人失望。免疫治疗策略的优化需要更好地了解炎症肿瘤的微环境。因此，我们研究的目的是对切除的胰腺癌和其他壶腹周围癌的淋巴细胞浸润模式进行详细的原位描述。将多路免疫荧光成像技术应用于175例切除壶腹周围腺癌患者的肿瘤组织微阵列。应用一组免疫细胞标记，包括CD4，CD8α，FoxP3，CD20，CD45RO和泛细胞角蛋白，以便同时对多个淋巴细胞群体进行空间分析。与胰胆管癌（PB型）相比，肠道（I型）中的大多数淋巴细胞群体明显丰富。层次聚类分析揭示了具有潜在临床意义的几种免疫细胞特征。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高和单阳性CD8α+ T细胞的低水平与总体生存期的改善相关（操作系统）。这项研究还定义了淋巴细胞浸润的预后相关地形图，特别是CD8α+细胞与癌细胞的接近程度。此外，在CD8α+细胞附近存在具有潜在T辅助能力（CD4 +）的淋巴细胞与OS延长有关。我们的数据表明壶腹周围腺癌中免疫浸润的成分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具有预后意义的潜在免疫学机制。