It is accepted that the microenvironment plays a crucial role in the development of tumors. The cellular microenvironment displayed only a few endogenous B-lymphocytes in lymphomatous eyes. Thus, the local cellular antitumoral response seems to be mainly based on CD3
+ T-lymphocytes, which represents up to 12% of the living cells. The molecular microenvironment of PIOL was also studied in our model. Patients with PIOL usually display high levels of IL-10 and an increased IL-10 to IL-6 ratio in their aqueous humor or in the vitreous, which has been shown to aid in the diagnosis of PIOL.
31 32 33 The origin of this immunosuppressive cytokine is currently attributed to tumor cells. IL-10 may participate in the prevention of immune rejection of the tumor (as an anti-inflammatory cytokine) and in lymphomatous cell proliferation (as a B-cell growth factor).
34 In our model, IL-10 was detected in eyes bearing tumor. The level of IL-10 in tumoral eyes was only slightly modified after T-cell stimulation, suggesting that IL-10 mainly originates from tumor cells rather than infiltrating Th2 and/or Tr1 T-cells. This finding is highlighted by the detection of IL-10 in lymphomatous B cells in vitro. Increasing evidence suggests that a polarized T-cell response of TILs, of either the Th1 or Th2-type, can be involved in tumor immunity or in tumor tolerance.
16 A partial Th1 cytokine profile of TILs was observed in supernatants of cultured ocular cells in the absence of any stimulation, characterized by the production of IFNγ and TNFα, but the absence of IL-2. Th2-specific cytokines such as IL-4 were not detected in the tumoral eyes, with the exception of IL-10, which may result from secretion by tumor cells. After in vitro stimulation of T-lymphocytes with anti-CD3
+ anti-CD28 antibodies, IL-2 production was induced, and IFNγ and GM-CSF were highly upregulated. Effector Th2 cytokines were still absent, since IL-4 level remained undetectable and IL-10 was only slightly upregulated. IL-12 and -4, required respectively for Th1 or Th2-polarization,
35 were undetectable in the supernatant of cultured cells, even after T-cell stimulation by anti-CD3
+ anti-CD28 mAbs. Thus, we hypothesize that the Th1/Tc1-type T-cells described earlier must have been polarized outside the eye, possibly in the draining lymph nodes. It has been shown that IL-10 exerts direct effects on human CD4
+ T-cell clones and on resting T-cells in peripheral blood, inducing specific inhibition of IL-2 production and proliferation.
36 This inhibitory effect of IL-10 could be an explanation of the status of partial inhibition of polarized TILs that we report in our model.