Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma
Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma
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DOI：
10.1002/ijc.32945
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发表时间：
2020-03-20
影响因子：
6.4
通讯作者：
Mezheyeuski, Artur
中科院分区：
文献类型：
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作者：
Lundgren, Sebastian;Elebro, Jacob;Mezheyeuski, Artur
免疫疗法目前正在彻底改变癌症治疗。然而，在胰腺癌方面，早期临床试验令人失望。免疫策略的优化需要更好地了解炎症肿瘤微环境。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。多重免疫荧光成像应用于组织微阵列与肿瘤从一个队列的175例切除壶腹周围腺癌。应用一组免疫细胞标志物，包括CD4、CD8 α、FoxP3、CD20、CD45 RO和泛细胞角蛋白，以允许同时进行多个淋巴细胞群的空间分析。大多数淋巴细胞群在肠道（I型）比胰胆（PB型）肿瘤更丰富。分层聚类分析揭示了几种具有潜在临床相关性的免疫细胞特征。值得注意的是，在PB型肿瘤的间质区室中，B细胞、CD8 α（+）CD45 RO（+）和单阳性CD4（+）T细胞的高浸润，但FoxP3（+）CD45 RO（高）和单阳性CD8 α（+）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细胞浸润的预后相关地形图模式，特别是CD8 α（+）细胞与癌细胞的接近度。此外，在CD8 α（+）细胞附近存在具有潜在T辅助细胞能力（CD4（+））的淋巴细胞与OS延长相关。我们的数据表明，壶腹周围腺癌中免疫浸润的组成和临床影响因形态学类型和定位而异。此外，空间原位分析确定了潜在的免疫学机制的预后意义。
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, CD8 alpha, 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, CD8 alpha(+)CD45RO(+) and single-positive CD4(+) T cells, but low levels of FoxP3(+)CD45RO(high) and single-positive CD8 alpha(+) T cells were associated with improved overall survival (OS). The study also defined prognostic relevant topographical patterns of lymphocytic infiltration, in particular proximity of CD8 alpha(+) cells to cancer cells. Moreover, the presence of lymphocytes with potential T-helper capacities (CD4(+)) in the nearest vicinity to CD8 alpha(+) 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.