Dynamic Observation: Immune-Privileged Microenvironment Limited the Effectiveness of Immunotherapy in an Intraocular Metastasis Mouse Model

Abstract

Introduction: Intraocular metastasis (IM) occurred in approximately 8-10% of patients with metastatic malignancy, for whom oncological immunotherapies showed poor visual potential. However, the mechanism for that inefficiency remains unclear and requires further exploration. Methods: we established a novel mouse model of intraocular metastasis by intracarotid injection of cutaneous melanoma cells. We investigated disease progression using ophthalmic and histological examinations. We used combined anti-PD-1 and anti-CTLA4 antibodies for immunotherapy and evaluate the therapeutic effects in mice model. In addition, we characterized the immune microenvironment of tumor infiltrating CD8+ T by fluorescence staining and assessed their cytotoxicity by flow cytometry. Results: All mice presented IM in the left eye, while the right eye was healthy. Uveal tissues with rich vascularity (e.g., the iris, ciliary body, and choroid) initiated intraocular metastasis at an early stage, and intraocular metastasis development resulted in several secondary changes, including corneal swelling, retinal detachment, and intratumoral haemorrhage. Immunotherapy could inhibit intraocular metastasis, prolong the time to eye rupture but did not prevent rupture ending. This inefficiency might be attributed to ocular tissues specificities that inhibited CD8+ T cells infiltration via PD-L1 expression. PD-L1low corneal tissue resisted tumor invasion with high levels of CD8+ T cells infiltration, whereas CD8+ T cells were deficient in PD-L1high uveal metastasis. Furthermore, we found a significantly increased PD-1+/- CD4+ and PD-1+/- CD8+ T cells infiltrating the intratumoral haemorrhage area. Although these CD8+ T cells in the IM were not exhausted and had a higher capacity of cytotoxicity (higher Interferon-γ ratio) than CD8+ T cells in the blood, FasL+ PD-L1+ ocular tissue can strongly inhibit these IM infiltrating T cells. Conclusions: Immunotherapy can inhibit the disease progression of intraocular metastasis. Enhancing the effects of tumor-infiltrating CD8+ T cells should be one of the highest potentials to improve the visual potential.

Integrating single-cell analysis and machine learning to create glycosylation-based gene signature for prognostic prediction of uveal melanoma

“…A growing number of studies have shown that TME is intimately connected to carcinogenesis and can, to some degree, predict tumor prognosis and the effectiveness of immunotherapy. The immune system is suppressed, and lymphatic circulation is restricted in the eye, which eventually causes the CD8+ T cell population to decline ( 34 , 35 ). High levels of M2-type macrophages and CD8 + T cells are found in the UM immune milieu in the GCNS_high group.…”

Transcriptome Analysis and Single-Cell Sequencing Analysis Constructed the Metastasis-Related Signature in Melanoma and Identified CD74 as a Novel Biomarker

“…Once metastasis has ocurred, the majority of cancers no longer warrant surgical therapy. Identifying molecular biomarkers of the various immune microenvironments stratifying metastatic melanoma would be useful for clinical treatment because patients with metastatic melanoma respond to immunotherapy with signi cant heterogeneity, primarily because of the heterogeneous tumor microenvironment (TME) [29]. Because melanoma is a typical immunogenic tumor, the number and kind of immune cells recruited by TME determine whether immune cell in ltration and prognosis are correlated.…”

Amebicides against Acanthamoeba castellanii: The Impact of Organism Models Used in Amebicide Assays

“…Immunological studies should not be ruled out for cases of keratitis. It is known that monoclonal antibodies are highly effective in several lines of treatment, such as autoimmune diseases and cancer [82], and because of their high specificity and efficacy for keratitis, it may be possible to develop immunotherapeutic ophthalmic solutions [7,78,79,83].…”