IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin

Abstract

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. IFNγ produced by tissue-infiltrating, antigen-specific CD8+ T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. Disruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine–Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

“…Tissue resident T cells that are retained in skin in a quiescent state are PD-1ehigh and activate protective immunity as a function of interaction with dendritic cells. Furthermore, PD-L1 expressed by lymphatic vessels contributes to T-cell accumulation such that loss of IFNgR on lymphatic vessels improves tumor control (Lane et al, 2018). This is just one of several surprising roles that IFNg plays in stratifying patients with melanoma (Nirschl et al, 2017).…”

Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

“…Antigen transported by lymphatic vessels can be presented by LECs, which use it to tolerize T cells [93]. Moreover, LECs actively dampen T cell mediated responses through PD-L1 expression [94]. The differential effects of lymphatic vessels on anti-tumor immunity must be considered with the use of anti-lymphangiogenic therapy.…”

Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

“…The lymphatic vasculature is also crucial for the initiation of tumor-specific T cell responses by facilitating antigen transport and DC migration from the tumor to the dLNs [ 115 , 116 ]. However, tumor-associated LVs restrain effector CD8 + T cell intratumoral accumulation through the upregulation of PD-L1 molecules [ 117 ] and the promotion of Treg suppressive functions locally in the tumor (Gkountidi et al, submitted). Interestingly, VEGF-C-induced lymphangiogenesis potentiates the response to immunotherapy [ 118 , 119 ] by favoring a CCL21-dependent naïve T cell infiltration into the tumor [ 119 ].…”