Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity

Abstract

The presence of lymph node (LN)-like vasculature in tumors, characterized by expression of peripheral node addressin and chemokine CCL21, is correlated with T-cell infiltration and positive prognosis in breast cancer and melanoma patients. However, mechanisms controlling the development of LN-like vasculature and how it might contribute to a beneficial outcome for cancer patients are unknown. Here we demonstrate that LN-like vasculature is present in murine models of melanoma and lung carcinoma. It enables infiltration by naïve T-cells that significantly delay tumor outgrowth after intratumoral activation. Development of this vasculature is controlled by a mechanism involving effector CD8 T-cells and NK cells that secrete LTα3 and IFNγ. LN-like vasculature is also associated with organized aggregates of B-lymphocytes and gp38+ fibroblasts that resemble tertiary lymphoid organs that develop in models of chronic inflammation. These results establish LN-like vasculature as both a consequence of and key contributor to anti-tumor immunity.

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…A high density of extra‐tumoral and intra‐tumoral Th1 cells correspond with improved survival,71 where it is proposed that their local priming, possibly within ELFs, promotes antigen‐specific tumour responses 72, 73. In murine models of melanoma and lung carcinoma, the development of lymph node‐like vasculature allows naive T‐cell entry into tumours that delay tumour outgrowth 74. Therefore modulation of HEV development or function through targeting LT α 1 β 2 to the tumour or by inhibiting Treg activity may provide opportunities for novel immunotherapies.…”

Innate immune signaling and regulation in cancer immunotherapy

“…This appears to be due to the presence in the tumors of vasculature resembling the high endothelial venules characteristic of lymph nodes. Through the expression of peripheral node addressins (PNAd) and CCL21 on the luminal endothelial surface, these blood vessels supported the extravasation of naive CD8 + T cells, which were subsequently activated in the tumor [48,49]. Thus, intratumoral expression of type I IFNs may even prompt tumor-infiltrating Batf3 DCs to cross-prime naive CD8 + T cells in the tumor, bypassing the need for migration to the draining lymph nodes.…”

Effector CD8 T-cell Entry into Subcutaneous and Intraperitoneal B16 Melanoma Tumors

“…Tumors that are poorly infiltrated by effector T-cells may be poorly immunogenic due to a paucity of antigens. Consistent with this, we have observed that murine B16 melanoma tumors transfected to express ovalbumin as a strong neo-antigen are infiltrated by larger numbers of effector CD8 T-cells than the parental B16 line, which is poorly antigenic (71). Similar results have been reported for other implantable murine tumors (72).…”