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Regulatory T cells (Treg) play a critical role in immune homeostasis by suppressing several aspects of the immune response. Herein, Glycoprotein A repetitions predominant (GARP), the docking receptor for latent transforming growth factor (LTGF-β), which promotes its activation, plays a crucial role in maintaining Treg mediated immune tolerance. After activation, Treg uniquely express GARP on their surfaces. Due to its location and function, GARP may represent an important target for immunotherapeutic approaches, including the inhibition of Treg suppression in cancer or the enhancement of suppression in autoimmunity. In the present review, we will clarify the cellular and molecular regulation of GARP expression not only in human Treg but also in other cells present in the tumor microenvironment. We will also examine the overall roles of GARP in the regulation of the immune system. Furthermore, we will explore potential applications of GARP as a predictive and therapeutic biomarker as well as the targeting of GARP itself in immunotherapeutic approaches.

Several types of cancer spread through the lymphatic system via the sentinel lymph nodes (LNs). Such LN-draining primary tumors, modified by tumor factors, lead to the formation of a metastatic niche associated with an increased number of Foxp3+ regulatory T cells (Tregs). These cells are expected to contribute to the elaboration of an immune-suppressive environment. Activated Tregs express glycoprotein A repetitions predominant (GARP), which binds and presents latent transforming growth factor beta 1 (TGF-β1) at their surface. GARP is also expressed by other non-immune cell types poorly described in LNs. Here, we mapped GARP expression in non-immune cells in human and mouse metastatic LNs. The mining of available (human and murine) scRNA-Seq datasets revealed GARP expression by blood (BEC)/lymphatic (LEC) endothelial, fibroblastic, and perivascular cells. Consistently, through immunostaining and in situ RNA hybridization approaches, GARP was detected in and around blood and lymphatic vessels, in (αSMA+) fibroblasts, and in perivascular cells associated with an abundant matrix. Strikingly, GARP was detected in LECs forming the subcapsular sinus and high endothelial venules (HEVs), two vascular structures localized at the interface between LNs and the afferent lymphatic and blood vessels. Altogether, we here provide the first distribution maps for GARP in human and murine LNs.