Comparison of the Cellular and Molecular Microenvironment Between Murine Primary Intraocular and Cerebral B-cell Lymphomas

Abstract

Purpose: : Non Hodgkin B-cell lymphomas (NHL) are usually localized in encapsulated or diffuse lymphoid organs. They can also arise in the eye (primary intraocular lymphomas, PIOL) or in the central nervous system (CNS) (primary cerebral lymphomas, PCL). These organs, protected respectively by the blood-retinal barrier and the blood-brain barrier, are usually considered as immune privileged sites. However, are they similar in their responses toward a tumor?

Methods: : To compare the immune response to a primary B-cell lymphoma in these privileged sites, we characterized the cellular and molecular immune microenvironments in a syngeneic murine model of PIOL or of PCL, using the same tumor cell-line (IIA1.6 lymphomatous cell-line). PIOL developed after intravitreal injection, whereas PCL developed after stereotaxic injection.

Results: : Our results showed that the brain, as the eye, was able to mount a similar immune response, with rapid and massive infiltration of CD4+ and CD8+ T-lymphocytes. In both models, cytokine profile analysis of the supernatant of ocular or cerebral cells cultured ex vivo (cytokine beads array) demonstrated the presence of IL10, IFNγ, and TNF. Stimulation of ocular cells with anti-CD3 plus anti-CD28 antibodies increased the IFNγ level, and led to the induction of IL2 production, completing the type 1 (Th1/Tc1-like) pattern of cytokine expression observed. IL12p70 and IL4, potent Th1 or Th2 differenciating factors, were undetectable even after stimulation.

Conclusions: : These results demonstrate that helper T-cell polarization is very similar in the eyes and the CNS, with preferential Th1-type cytokine production. However, in both cases infiltrating T-lymphocytes disclose a partially impaired cytokine profile, which can be reactivated upon T-cell stimulation. This suggests that even if immune responses are constitutively down modulated in the eye or in the brain to protect the neuronal populations, these organs are able to recruit the main actors of a classical anti-tumor immune response. Anti-tumoral immune manipulations proposed in PIOL should thus be good candidates for brain lymphomas.

Keywords: tumors • immunomodulation/immunoregulation • oncology