Using PD-L1-/- bone marrow chimeras, Lane et al. found that both hematopoietic and non-hematopoietic PD-L1 expression contributes to immunosuppression in mouse melanoma. Notably, lymphatic endothelial cells (LECs) locally upregulate PD-L1 in cancer and viral infection in response to CD8+ T cells. Mice with LEC-specific IFNγR knockout showed reduced LEC PD-L1 expression and increased T cell infiltrate, resulting in elevated pathology in infection and improved tumor control. In human melanoma, lymphatic cell and CTL gene expression correlated, and CD8+ T cells spatially organized with lymphatic vessels in the tumor periphery.
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. IFNgamma 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 IFNgamma-dependent crosstalk through lymphatic-specific loss of IFNgammaR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNgammaR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.
Author Info: (1) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. (2) Department of Cell, Developmental and Cancer Biology, Oregon Healt
Author Info: (1) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. (2) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. (3) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. (4) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. (5) Department of Biomedical Engineering and Computational Biology Program, Oregon Health and Science University, Portland, OR. OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR. (6) Knight Cancer Institute, Biostatistics Shared Resource, Oregon Health and Science University, Portland, OR. (7) Knight Cancer Institute, Biostatistics Shared Resource, Oregon Health and Science University, Portland, OR. (8) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR. Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan. (9) Department of Biomedical Engineering and Computational Biology Program, Oregon Health and Science University, Portland, OR. OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR. (10) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR lunda@ohsu.edu. OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR. Department of Dermatology, Oregon Health and Science University, Portland, OR. Knight Cancer Institute, Oregon Health and Science University, Portland, OR.
