Perivascular expression of CXCL9 and CXCL12 in primary central nervous system lymphoma: T-cell infiltration and positioning of malignant B cells

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.