Zbtb46coordinates angiogenesis and immunity to control tumor outcome

Abstract

AbstractTumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. An inverse correlation of these two1hints at common regulatory mechanism(s). Here, we report thatZbtb46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2, 3, constitutes one such regulatory mechanism.Zbtb46was downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth.Zbtb46downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of lowZBTB46expression with an immunosuppressive TME and a worse prognosis. In contrast, enforcedZbtb46expression mitigated the pro-tumor TME features and restricted tumor growth. Mechanistically,Zbtb46-deficient ECs were highly angiogenic, andZbtb46-deficient bone-marrow progenitors upregulatedCebpband diverted the DC program to myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4–7. Conversely, enforcedZbtb46expression normalized tumor vessels and, by suppressingCebpb, skewed bone-marrow precursors towards more DC generation over macrophages, leading to an immune-hot TME. Remarkably,Zbtb46mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identifyZbtb46as a common regulatory mechanism for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.