Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Front Immunol. 2018 Sep 12;9:2084. doi: 10.3389/fimmu.2018.02084. eCollection 2018.
The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely important to mount effective distant responses and for the establishment of long term systemic memory. Looking into mechanisms behind lymphocyte egress, we directed our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion in mouse models of melanoma and breast cancer. We also provide evidence of the presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1 interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+ T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic receptor CCR7 augments in tumor infiltrating lymphocytes and in de-clustered T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve the transit of activated lymphocytes toward the lymph nodes and their subsequent recirculation.
淋巴细胞从肿瘤进入引流淋巴结的数量对于产生有效的远端反应和建立长期的全身记忆可能很重要。为了研究淋巴细胞迁出的机制，我们将注意力转向肿瘤内白细胞黏附机制。在这里，我们证明在黑色素瘤和乳腺癌的小鼠模型中，活化的 T 细胞以 LFA-1-ICAM-1 依赖性方式在肿瘤内形成聚集。我们还提供了原发性人类黑色素瘤中存在 T 细胞簇的证据。破坏 LFA-1-ICAM-1 相互作用，从而破坏 T 细胞聚集，可增强活化的 CD8+T 细胞在移植和自发性癌症模型中到达肿瘤引流淋巴结的数量。有趣的是，在阻断 ICAM-1 后，趋化性受体 CCR7 在肿瘤浸润淋巴细胞和去聚集的 T 细胞中的表达增加，以及它们穿过淋巴管内皮细胞的迁移能力也增加。我们提出，ICAM-1 介导的同型 T 淋巴细胞聚集可能作为一种肿瘤介导的免疫保留机制，将活化的 CD8+T 细胞困在肿瘤微环境中。调节 T 细胞黏附可能有助于改善活化淋巴细胞向淋巴结的迁移及其随后的再循环。
