Institute for Research in Biomedicine, Bellinzona, Switzerland.
Int J Cancer. 2010 Nov 15;127(10):2300-12. doi: 10.1002/ijc.25236.
Primary central nervous system lymphomas (PCNSL) are aggressive malignancies confined to the CNS, mostly of diffuse large B-cell histotype. Despite improved understanding of the malignant B cells, little is known on the tumor microenvironment and on the response of the adaptive immunity against PCNSL. We investigated the phenotype of tumor infiltrating lymphocytes (TILs), and the expression of chemokines that could affect malignant B cells and trafficking of TILs. TILs and chemokine expression were evaluated by immunohistochemistry and in situ hybridization. Furthermore, we performed in vitro migration assays to analyze the migratory capacity of lymphocytes and malignant B cells toward chemokines and chemokine heterocomplexes. We show in 22 cases of PCNSL from immunocompetent patients that CD8(+) T cells represent the majority of TILs in the tumor mass. They tend to accumulate in perivascular areas, show Granzyme B expression and proliferate in situ. Their localization and density correlates with the expression of the inflammatory chemokine CXCL9, which is transcribed and translated by perivascular macrophages and pericytes in the perivascular microenvironment. Moreover, CXCL9 and CXCL12 are coexpressed on the tumor vasculature and form heterocomplexes. In the presence of CXCL9, CXCL12-induced migration is enhanced not only on CXCR4(+)/CXCR3(+)/CD8(+) T cells but also on CXCR4(+)/CXCR3(-) malignant B cells. These findings indicate the presence of a strong chemoattractant stimulus in the perivascular microenvironment, which might serve as regulator for the recruitment of TILs and for the angiocentric positioning of malignant B cells in the perivascular cuff.
原发性中枢神经系统淋巴瘤（PCNSL）是局限于中枢神经系统的侵袭性恶性肿瘤，主要为弥漫性大 B 细胞组织学类型。尽管人们对恶性 B 细胞有了更好的了解，但对于肿瘤微环境以及适应性免疫对 PCNSL 的反应知之甚少。我们研究了肿瘤浸润淋巴细胞（TIL）的表型，以及可能影响恶性 B 细胞和 TIL 迁移的趋化因子的表达。通过免疫组织化学和原位杂交评估 TIL 和趋化因子的表达。此外，我们进行了体外迁移实验，以分析淋巴细胞和恶性 B 细胞向趋化因子和趋化因子异源复合物的迁移能力。我们在 22 例免疫功能正常的 PCNSL 患者中显示，CD8(+) T 细胞是肿瘤块中 TIL 的主要组成部分。它们倾向于在血管周围区域积聚，表现出 Granzyme B 表达并在原位增殖。它们的定位和密度与炎症趋化因子 CXCL9 的表达相关，该因子由血管周围巨噬细胞和周细胞在血管周围微环境中转录和翻译。此外，CXCL9 和 CXCL12 在肿瘤血管上共表达并形成异源复合物。在 CXCL9 的存在下，CXCL12 诱导的迁移不仅增强了 CXCR4(+)/CXCR3(+)/CD8(+) T 细胞，而且增强了 CXCR4(+)/CXCR3(-)恶性 B 细胞的迁移。这些发现表明，血管周围微环境中存在强烈的趋化刺激，可作为招募 TIL 和将恶性 B 细胞定位于血管周围袖套的调节剂。
