Modulation of tumor vasculature promotes tertiary lymphoid organogenesis.

Abstract

Abstract The tumor vasculature has been shown to have pro-tumorigenic effects, leading to the use of anti-angiogenic drugs as therapy. However, the importance of tumor vasculature in recruiting immune cells to the tumor microenvironment (TME), leading to the formation of tertiary lymphoid structures (TLS) within the TME, has also been shown. TLS are aggregates of immune cells that develop at site of chronic inflammation and function as local sites of immune priming. The presence of TLS in the TME is a positive prognostic marker in many human tumors, suggesting that modulation of the tumor vasculature to promote increased TLS formation may serve as a novel therapeutic modality for solid tumors. We have previously shown that intratumorally-injected dendritic cells (DC) engineered to overexpress the Type 1 transactivator Tbet (DC.Tbet) slow tumor progression in a mouse model dependent on T and NK cell recruitment to the TME. Our recent work indicates that DC.Tbet treatment of established murine sarcomas and colon carcinomas leads to an upregulation by d5 following treatment of peripheral node addressin (PNAd) on CD31+ vascular endothelial cells, marking high endothelial venules (HEV) similar to those found in lymph nodes. Dense infiltrates of T cells and DC surround these HEV; however, T cells and DC are observed proximal to tumor vasculature before PNAd upregulation is observed, indicating that while HEV mark mature TLS, PNAd does not initiate TLS formation. Instead, we observe that DC.Tbet but not unmodified DC express CCL21, CXCL13, lymphotoxin (LT) α, and LIGHT. In vivo these can recruit and activate DC, T cells, NK cells, and B cells, which can modulate the vasculature via LT signaling axes to upregulate PNAd and propagate immune cell recruitment to TLS.