Hijacking the Blimp1-Neuritin Axis to Promote Cancer by Follicular Regulatory T-cells

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Project Summary Recent studies have highlighted the vital role of nerves infiltrating the tumor microenvironment (TME) in tumorigenesis and caner progression. The current research in this field is largely focused on the impact of dysfunctions of autonomic nervous system or psychological stress-induced hormone network on the malignant progression of cancer. The potential regulation of peripheral nerve system by immune cells in the TME, which subsequently influences tumorigenesis, has not been extensively studied. The overall goal of this proposal is to define how a specific Treg subset, called follicular regulatory T (TFR) cells, modulates the TME to promote cancer by producing and utilizing a neurotrophic factor, which is an unexplored area in the field of cancer research. We have recently reported the pro-tumoral activity of TFR cells, which depends on the expression of the transcription factor Blimp1 (encoded by Prdm1). Further analysis revealed that higher tumoral TFR signatures along with PRDM1 expression indicated increased malignancy and risk of metastasis in many cancers. Moreover, intratumoral TFR cells compared to conventional Treg cells and their peripheral counterparts expressed higher levels of neuritin (encoded by Nrn1), a neurotrophic factor implicated in tumorigenesis, while its mechanistic action remains largely unclear. Notably, TFR signature and PRDM1 positively correlated with NRN1 expression in cancer patients. Intratumoral TFR cells in mice with disrupted TFR suppression due to Foxp3-specific deletion of Blimp1 had substantially reduced expression of neuritin. Most importantly, tumors from these mice and mice lacking TFR cells had markedly reduced neurofilament accumulation compared to wild-type tumors, and intratumoral TFR cells were enriched with gene signatures implicated in axonogenesis. We propose to define the mechanisms by which TFR cells exploit the Blimp1-neuritin axis to regulate the TME and tumor progression, and to define the capacity of TFR-derived neuritin in promoting axonogenesis in the tumor. Findings obtained here will revolutionize our understanding of the tumor innervation and immunosuppressive TME, aiding in developing new immunotherapeutic approaches to treat cancer.