Analysis of cancer-related immune suppressor mechanisms in mice

Division Of Basic Sciences - Nci

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Abstract

We have mirroed a clinical trial we conducted in patients with cholangiocarcinoma using a combination of anti-VEGF/anti-CTLA4/anti-PD-L1 after seeing exceptional responses in patients. We demonstrated that VEGF blockade in combination with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) + anti-programmed death-ligand 1 (PD-L1) in cholangiocarcinoma (CCA) potentiated a multimodal mechanism dependent on B cell activating factor (BAFF), leading to a proinflammatory B cell response. It led to a BAFF- and interleukin (IL)-12-dependent expansion and rewiring of T regulatory cells (Tregs) toward an anti-tumor T helper-1 (Th-1)-like fragile state. We translated this approach to the clinic and observed immunological changes characterized by Treg cell expansion and rewiring toward fragile and unstable states. We explored the effect of VEGF receptor 2 (VEGFR2) signaling on Treg cell transcriptional programming and established a mouse model ablating VEGFR2 expression on Treg cells. In summary we described a totally novel mmunological mechanism by which targeting VEGF induced strong immune responses together with CTLA-4 and PD-L1 blockade.