TY - JOUR
T1 - Perivascular expression of CXCL9 and CXCL12 in primary central nervous system lymphoma
T2 - T-cell infiltration and positioning of malignant B cells
AU - Venetz, Daniel
AU - Ponzoni, Maurilio
AU - Schiraldi, Milena
AU - Ferreri, Andrés J M
AU - Bertoni, Francesco
AU - Doglioni, Claudio
AU - Uguccioni, Mariagrazia
PY - 2010/11/15
Y1 - 2010/11/15
N2 - 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.
AB - 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.
KW - cell migration
KW - chemokines
KW - DLBCL
KW - PCNSL
KW - perivascular microenvironment
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U2 - 10.1002/ijc.25236
DO - 10.1002/ijc.25236
M3 - Article
C2 - 20872671
AN - SCOPUS:78049502210
VL - 127
SP - 2300
EP - 2312
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 10
ER -