The roles of tumor associated macrophages and interferon gamma in immune surveillance in CNS lymphoma (P2211)

Abstract

Abstract The distinctive roles of macrophages in cancer are believed to reflect selective M1 or M2 states of differentiation. Central nervous system lymphomas (CNSL) are aggressive tumors with poor prognosis. We generated murine CNSL models to elucidate the role of the immune microenvironment, especially macrophages, in this disorder. We determined that the majority of tumor-associated macrophage (TAM) expressed the mannose receptor CD206, an established M2 marker, and showed phagocytic activity of lymphoma. Surprisingly, this phenotype of TAM was also observed in mice deficient in IL-4, IL-4Ra, IL-10, or STAT6, suggesting that the M2-like feature of TAM was not driven by Th2 pathways. Few TAM were noted to express arginase I, another M2 marker. We also found upregulation of M1 markers MHCII and nitric oxide on TAMs, indicating a M1/M2 intermediate phenotype. CNSL progressed more rapidly In IFNγ-/- Rag-/- mice than in Rag-/- mice. Furthermore, macrophage depletion significantly exacerbated CNSL progression, but failed to do so in IFNγ deficient mice, suggesting that IFNγ-primed macrophage inhibits tumor growth in CNSL. Reduction of macrophage infiltration to tumor site promoted CNSL progression. Distinct from the CD45loCD11blo microglias, TAMs were CD45hiCD11bhi and maintained Ly6C, suggesting a monocytic origin of these cells. Based upon this data we report that CNSL TAMs present both M1 and M2 features and may mediate immune surveillance against lymphoma progression in brain.