The role of chronic neuroinflammation in the pathogenesis of CNS lymphoma
Final Report Abstract
The 1-year overall survival rate of peripheral diffuse large B cell lymphoma (DLBCL) is ∼85%. However, prognosis of patients with primary central nervous system lymphoma (PCNSL) is markedly poorer, with a one-year overall survival rate of 50%-60%. Lymphoma also disseminate to the central nervous system (CNS) from peripheral sites at a rate of 4%- 5% (“secondary” CNSL [SCNSL]), and the prognosis for SCNSL is typically even poorer. Since the advent of anti-retroviral therapy, HIV-associated CNSL has become less common. Hence, the majority of CNSLs currently occur in immunocompetent individuals, and it is unclear how or why malignant cells of lymphoid origin invade the nervous tissue. Chronic inflammatory conditions elevate the risk for developing peripheral lymphomas. A similar epidemiological link between neuroinflammation and a heightened risk for CNSL has not been reported. How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
Publications
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Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention. Cancer Cell, 36(3), 250-267.e9.
O.'Connor, Tracy; Zhou, Xiaolan; Kosla, Jan; Adili, Arlind; Garcia, Beccaria Maria; Kotsiliti, Elena; Pfister, Dominik; Johlke, Anna-Lena; Sinha, Ankit; Sankowski, Roman; Schick, Markus; Lewis, Richard; Dokalis, Nikolaos; Seubert, Bastian; Höchst, Bastian; Inverso, Donato; Heide, Danijela; Zhang, Wenlong; Weihrich, Petra; ... & Heikenwalder, Mathias
