High endothelial venules as potential gateways for therapeutics

High endothelial venules (HEVs) are specialized mammalian segments of vasculature that are specific to secondary lymphoid organs and hence represent potential targets for immunotherapeutics. Antibodies that bind selectively to HEVs provide efficient targeting tools for immunotherapeutics through conjugation or encapsulation inside HEV antibody-coated nanocarriers. HEVs can also develop in organ tissues in association with autoimmune and immune-mediated disorders, including transplant rejection; they are also often found in conjunction with tertiary lymphoid organs in humans and mice. Located proximal to primary tumors, tumor-draining lymph nodes, and metastatic lesions in humans and mice, tumor-associated HEVs provide a rationale for the development of potential HEV-targeted, drug-specific delivery to cancer patients. High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases. High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases. T lymphocytes that express a genetically engineered CAR. CAR T cells can bind to a specific protein, such as those expressed by malignant cells, and trigger T cell activation. CAR-T therapy has been effective in allogeneic and autologous treatment against certain types of cancer. typical HEV lined by cuboidal HECs that are responsible for facilitating lymphocyte extravasation. HEV subtype found surrounding human melanoma tumors. The presence of this HEV may represent the late quiescent stage of the antimelanoma immune response. examples are PD-1 and CTLA-4, which are extracellularly expressed proteins on T lymphocytes. Activation of immune checkpoints such as PD-1 downregulates T cell activity. Immune checkpoint inhibitors oppose the activity of immune checkpoint proteins, thus preventing T cell downregulation, and have been used to promote antitumor immunity for certain cancers. contain the Ins1-GAS transgene and overexpress gastrin in the pancreas; well-suited models for gastric cancer. series of glycoproteins found on the surface of HECs that are ligands for L-selectin expressed by lymphocytes; enable their interaction with HECs. GlyCAM-1, CD34, sbp200, podocalyxin, endomucin, and nepmucin are all members of this group. sites in which immune responses are initiated and maintained to generate protective immunity against exogenous pathogens and tolerance to self-antigens and commensal organisms. These specialized structures include LNs, Peyer’s patches, tonsils, and spleen. The blood vasculature in lymphoid organs differs from that found in other organs due to the requirement for efficient recruitment of lymphocytes under non-inflammatory, homeostatic conditions. HEVs perform this function in all SLOs except the spleen. method to isolate single cells, capture transcripts, and generate sequencing libraries in which transcripts are mapped to individual cells. collection of mRNA molecules expressed by an organism; also used to define the array of mRNA transcripts produced in a particular cell or tissue type.