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Divergent local and systemic antitumor response in primary uveal melanomas

ABSTRACT: Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome-3 (M3) is associated with high risk of metastases. M3-tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T-cell infiltration correlates with better prognosis. Whether these T-cells represent an anti-tumor response and how these T-cells would be primed in the eye are both unknown. Herein, we characterized the T-cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3- than in D3-tumors. CD39+PD-1+CD8+ T-cells were enriched in M3-tumors suggesting specific responses to tumor-antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. ScRNAseq-VDJ analysis of T-cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions suggesting in-situ anti-tumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the anti-tumor responses in M3- and D3-tumors. Thus, tumor-Ag responses occur in localized UMs raising the question of the priming mechanisms in the absence of known lymphatic drainage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248838 | GEO | 2024/03/23

REPOSITORIES: GEO

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Project description:Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)-γ and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFNγ, FasL and CD8+ T cells but not perforin or TNFα were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras showed that immune cell expression of IFNγR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFNγ- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors. C57BL/6 mice that were splenectomized (Tumor_splnx) or were not surgically manipulated (Tumor_intact) were challenged with 10^4 luciferase-expressing E.G7-OVA cells injected into the anterior chamber of the eye. Fifteen days later, the animals were euthanized and tumor-bearing eyes were removed.

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Divergent local and systemic antitumor response in primary uveal melanomas

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