Correction: Lymphatic transport in anti-tumor immunity and metastasis

Under CCL21 guidance, CCR7+ DCs migrate from the tissues to the lymphatic capillaries (Russo et al., 2016; Tal et al., 2011; Weber et al., 2013). Interestingly, steady-state DCs autonomously migrate into the LVs mainly by flowing and squeezing (Lämmermann et al., 2008) (Fig. 2 a). The sole force of actin-network expansion promotes protrusive flowing of the leading edge, whereas the myosin II–dependent squeezing contraction of the trailing edge propels the rigid nucleus and allows the passage through narrow gaps, which is sufficient to drive DC locomotion (Lämmermann et al., 2008). This process only becomes integrin receptor/ligand dependent under inflammatory conditions when LECs upregulate ICAM-1 and VCAM-1, such as through integrin and ICAM-1/VCAM-1 interactions (Arasa et al., 2021; Johnson et al., 2006) (Fig. 2 b), or via LYVE-1/hyaluronan (HA) axis–mediated transmigration (Fig. 2 b) (Johnson et al., 2017). Recent findings show that in case of inflammation, the connective tissue membrane surrounding the lymphatic collectors is subjected to degradation, whereas the collectors upregulate the DC-trafficking molecule VCAM-1, facilitating DC penetration and rapid transportation to draining LNs (Arasa et al., 2021) (Fig. 2 c). After reaching the LNs, DCs first enter the LN subcapsular sinus. Ceiling LECs produce ACKR4 (or CCRL1), a decoy receptor for CCL21 and CCL19, that scavenges these chemokines in the sinus lumen and shapes chemokine gradients directed toward the floor layer. Some studies indicate that in some contexts, CCR7 may not be sufficient for proper DC positioning within the LN and that other chemokine networks may be involved in subset-specific DC migration to LNs. For example, Th2-skewing stimulus efficiently induces the migration of CD301b⁺ DCs into draining LNs despite low surface CCR7 levels. Instead, CD301b⁺ DCs upregulate CCR8, and their migration toward the LN parenchyma is facilitated by floor LECs that produce CCL1 (Qu et al., 2004; Sokol et al., 2018) (Fig. 2 d).

Apart from supporting cell transportation, LVs actively contribute to immunosurveillance and immunomodulation. Human and mouse LN LECs express MHC class I (MHC-I) and MHC-II. At steady state, LN LECs endogenously express peripheral tissue–restricted antigens that they can present through MHC-I (Johnson et al., 2017; Olszewski, 2005), inducing the deletion of autoreactive CD8⁺ T cells and therefore participating in peripheral T cell tolerance (Cohen et al., 2010; Fletcher et al., 2010; Tewalt et al., 2012). LECs can also cross-present exogenous antigens via MHC-I to induce antigen-specific CD8⁺ T cell apoptosis (Hirosue et al., 2014). Although LECs seem unable to present antigens through MHC-II due to the absence of the H2-M expression at steady state (Rouhani et al., 2015), they can induce antigen-specific CD4⁺ T cell tolerance by presenting peptide–MHC-II complexes acquired from DCs or by presenting peptides through IFN-γ–induced endogenous MHC-II under inflammatory condition (Dubrot et al., 2014). For example, MHC-II deficiency in LN LECs promotes defective Tregs and increased effector CD4⁺ T cells, resulting in impaired peripheral CD4⁺ T cell tolerance and enhanced autoantibody production in aging mice (Dubrot et al., 2018). Furthermore, S1P produced by LN LECs supports naive T cell survival through the stimulation of their mitochondrial function (Mendoza et al., 2017). LECs express IL-7 in both LN and peripheral tissues, suggesting that they might support T cell survival (Hara et al., 2012). Under infection and inflammation, some factors released into the surrounding tissue activate LECs to induce their proliferation, a process called lymphangiogenesis. These factors, named lymphangiogenic factors, promote LEC proliferation, sprouting, and activation, altogether increasing the abundance of LVs in inflamed tissues. LVs experience remarkable expansion, accompanied by a transient increase of lymph flow, promoting the translocation of DCs and lymphocytes to the LN parenchyma and therefore the initiation of the immune response. Extranodal lymphangiogenesis is accompanied by intranodal lymphangiogenesis in the LNs draining the inflamed tissue, which can be reverted by a T cell–dependent IFN-γ–mediated negative regulation (Kataru et al., 2011). Upon inflammatory stimuli, LN LECs further express immunosuppressive enzymes, such as indoleamine dioxygenase and inducible nitric oxide synthase (iNOS), thereby suppressing T cell proliferation and activation (Lukacs-Kornek et al., 2011), as well as inhibiting DC maturation (Christiansen et al., 2016). During viral infection and vaccination, LN LECs function as antigen-archiving cells and slowly release these antigens into the LN parenchyma to contribute to protective immune responses (Kedl et al., 2017; Tamburini et al., 2014). During bacterial infection, such as Mycobacterium tuberculosis, the bacteria can be transported and internalized by LN LECs, in which bacterial proliferation is inhibited by the production of nitric oxide by LECs when exposed to IFN-γ (Lerner et al., 2016). Tumors are a typical condition where lymphangiogenesis occurs andwhere some of the remodeling of LEC features described above might apply, together with specific adaptations induced by the tumor microenvironment (TME) (developed in Lymphangiogenic factors in the TME).