Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer

Abstract

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.

Identification of bladder cancer subtypes and predictive model for prognosis, immune features, and immunotherapy based on neutrophil extracellular trap-related genes

“…The involvement of Hedgehog signaling in the regulation of Treg differentiation and activity, as well as the transition between Tregs and Th17 cells within the tumor microenvironment, has been identified. Additionally, the processes of EMT and angiogenesis have been recognized as pivotal factors in cancer metastasis 39 . These processes collectively facilitate the departure of cancer cells from the primary tumor, invasion into neighboring tissues, dissemination to distant organs, and ultimately contribute to the progression and metastatic dissemination of malignant tumors 40 , 41 .…”

Heme Oxygenase-1 Expression in Dendritic Cells Contributes to Protective Immunity against Herpes Simplex Virus Skin Infection

“…To our knowledge, HO-1 expression in DCs has not been related to the promotion of a Th17 phenotype in CD4 + T cells; yet again, this may be a particular phenomenon related to viral infections, and more specifically, to HSV infection, that has been scarcely studied [ 27 , 69 ]. Since Th17 cells have been reported to be plastic in terms of their capacity of acquiring features associated with other Th phenotypes, such as those related to Th1 cells or Tregs, the implications of our findings could relate to HO-1 expression in DCs, conferring these cells to have the ability to fine-tune Th responses with favorable outcomes regarding HSV infection [ 70 , 71 ]. Interestingly, we observed mixed populations of T cells including CD4 + T cells that were both RORγt- and FoxP3-positive, which has been related to a trans-differentiation state between Tregs and Th17 cells [ 49 , 72 , 73 ].…”

Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases

“…Additionally, the Hh signalling pathway promotes Treg differentiation by upregulating the expression of transcription factor Foxp3. Inhibition of the Hh signalling pathway suppresses the immunosuppressive activity of Treg cells and promotes the transformation of Tregs to Th17 cells ( 68 ). Xiao et al.…”