Tumor-Associated Lymphatic Vessels Upregulate PDL1 to Inhibit T-Cell Activation

Abstract

Tumor-associated lymphatic vessels (LVs) play multiple roles during tumor progression, including promotion of metastasis and regulation of antitumor immune responses by delivering antigen from the tumor bed to draining lymph nodes (LNs). Under steady-state conditions, LN resident lymphatic endothelial cells (LECs) have been found to maintain peripheral tolerance by directly inhibiting autoreactive T-cells. Similarly, tumor-associated lymphatic endothelium has been suggested to reduce antitumor T-cell responses, but the mechanisms that mediate this effect have not been clarified. Using two distinct experimental tumor models, we found that tumor-associated LVs gain expression of the T-cell inhibitory molecule PDL1, similar to LN resident LECs, whereas tumor-associated blood vessels downregulate PDL1. The observed lymphatic upregulation of PDL1 was likely due to IFN-g released by stromal cells in the tumor microenvironment. Furthermore, we found that blocking PDL1 results in increased T-cell stimulation by antigen-presenting LECs in vitro. Taken together, our data suggest that peripheral, tumor-associated lymphatic endothelium contributes to T-cell inhibition, by a mechanism similar to peripheral tolerance maintenance described for LN resident LECs. These findings may have clinical implications for cancer therapy, as lymphatic expression of PDL1 could represent a new biomarker to select patients for immunotherapy with PD1 or PDL1 inhibitors.

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

“…Our results are striking in terms of the strong inflammatory gene expression signature of 4T1‐associated LECs, which included induction of many chemokines and adhesion molecules. We also found a trend (log 2 FC = 1.96, FDR = 0.68) toward increased expression of the T cell inhibitory protein PD‐L1, which is in line with our own previous observations . Clearly, this proinflammatory gene expression signature is likely to have a plethora of effects on tumor progression, metastasis and host immunity.…”

“…Cell suspensions of control skin, 4T1 tumors and tumor‐draining LNs were prepared as described . For staining, the following antibodies were used: CD45‐APC/Cy7 or CD45‐PacificBlue (Biolegend 103116, 103126), CD31‐APC (BD 551262), podoplanin‐PE (eBioscience, San Diego, CA, 12‐5381‐82), CD3‐PE/Cy7 (Biolegend 100220), CD11b‐BV605 (Biolegend 101257), Ly6C‐PE (Biolegend 128008), Ly6G‐FITC (Biolegend 127606), F4/80‐Alexa647 (BioRad MCA497G), VE‐cadherin‐APC (Biolegend 138012) and goat antimouse VCAM‐1 (R&D AF643), followed by washing and labeling with a secondary donkey antigoat‐Alexa488 antibody.…”

Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

“…In a murine model of lymphatic-enriched melanoma, we have found that VEGF-Cstimulated LECs in the tdLNs tolerize antitumor CD8 + T cells through cross-presentation of tumor Ags [182]. Very recently, PD-L1 expression by LECs was shown to have a crucial role in the inhibition of CD8 + T cell response in the context of tumor [220]. These studies underline the ability of LECs to extend their Ag presentation abilities beyond PTAs, therefore broadening their role as an active player in immune responses.…”

Heterogeneity of tumor lymphangiogenesis: Progress and prospects

“…An increase in VEGF‐C expression in tumors is highly correlated with LN metastasis and poor prognosis in individuals with different tumor types, including skin, breast and lung cancers . Furthermore, LEC not only present antigens and modulate immune cell activation in physiology conditions but also promote tumor progression and metastasis by inhibiting the function of immune cells (Figure ) . Mechanistically, VEGF‐C plays an immunosuppressive role for LEC to scavenge and cross‐present antigens for direct suppression of cytotoxic T lymphocytes .…”

“…2 Furthermore, LEC not only present antigens and modulate immune cell activation in physiology conditions 64,65 but also promote tumor progression and metastasis by inhibiting the function of immune cells (Figure 3). 40,66 Mechanistically, VEGF-C plays an immunosuppressive role for LEC to scavenge and cross-present antigens for direct suppression of cytotoxic T lymphocytes. 61 LEC can also express immunosuppressive factors such as TGF-β and nitric oxide to maintain peripheral tolerance to self-antigens in lymph nodes by directly or indirectly regulating T-cell fate and function in immunity.…”