Treg Depletion Licenses T Cell–Driven HEV Neogenesis and Promotes Tumor Destruction

Abstract

T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process which can increase frequencies of tumor-infiltrating lymphocytes (TILs) through promoting development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model, that allows for co-evolution of the tumor microenvironment and the immune response, to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on TNF receptor and independent of lymphotoxin β receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer.

Regulation of regulatory T cells in cancer

“…High endothelial venules (HEV) which can be associated with tertiary lymphoid structures are present within tumours. The presence of HEV is promoted by activation of Tconv cells and dependent upon tumour necrosis factor receptor signalling . As HEV themselves drive further T‐cell recruitment, it has been proposed that this supportive relationship between Tconv cells and HEV forms the potential for a self‐amplifying loop that can drive tumour destruction.…”

“…As HEV themselves drive further T‐cell recruitment, it has been proposed that this supportive relationship between Tconv cells and HEV forms the potential for a self‐amplifying loop that can drive tumour destruction. HEV neogenesis is indirectly inhibited by Treg cells through their suppression of Tconv cell activation . However, tertiary lymphoid structures contain Treg cells and whether and how HEV play an active role in recruitment of Treg cells is unclear.…”

“…The presence of HEV is promoted by activation of Tconv cells and dependent upon tumour necrosis factor receptor signalling. 87 As HEV themselves drive further T-cell recruitment, it has been proposed that this supportive relationship between Tconv cells and HEV forms the potential for a self-amplifying loop that can drive tumour destruction. HEV neogenesis is indirectly inhibited by Treg cells through their suppression of Tconv cell activation.…”

“…HEV neogenesis is indirectly inhibited by Treg cells through their suppression of Tconv cell activation. 87 However, tertiary lymphoid structures contain Treg cells 88 and whether and how HEV play an active role in recruitment of Treg cells is unclear. L-selectin expression is required for appropriate trafficking and tissue distribution of Treg cells under physiological conditions.…”

Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer

“…In breast cancer and melanoma, the density of HEV correlated with improved patient outcome highlighting the important role that HEV play in orchestrating anti-cancer immunity (20,21). HEV neogenesis correlates with regression of established tumours in preclinical mouse tumour immunotherapy models, such as depletion of Foxp3 + regulatory T cells (22,23) or combined checkpoint blockade inhibition and angiogenesis therapy (24). HEV neogenesis and tumour regression are also seen when the TNF superfamily member LIGHT (TNSF14) (which signals via LTβR, an important driver of lymphoid organ development) is expressed by tumour cells or targeted to tumours or tumour blood vessels (25)(26)(27).…”