Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer (Oncoimmunology 2019, 8(3):1548241.)

報告日期: 2019/10/18
報告時間: 15:10/16:00
報告學生: 譚凱霖
講評老師: 洪澤民
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Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer

Ann Hanna, Brandon J. Metge and Sarah K. Bailey, et al

Oncoimmunology 2019, VOL. 8, NO. 3

Speaker: Hoi-Lam Tam (譚凱霖)                               Time: 18th October, 2019 15:10–16:00

Commentator: Prof. Tse-Ming Hong (洪澤民教授)       Place: Room 602

Abstract

        The tumor microenvironment (TME) is a complex network which consists multiple cell types such as epithelial cells, immune cells and fibroblasts that participate in crosstalk with tumor cells and playing a major role in regulating tumor growth and progression. In solid tumors, tumor associated macrophages (TAMs) comprise approximately 50% of the tumor mass. Peripheral blood monocytes are recruited and differentiate into macrophages in response to various chemokines and growth factors produced by stromal and tumor cells in the tumor microenvironment. Increasing evidence indicates the enrichment of infiltrating macrophages in breast tumor microenvironment correlates with higher tumor grade and lower survival rate in patients.1 Hedgehog (Hh) signaling is an important pathway for normal mammalian development.2 Hedgehog signaling molecules in mammal include three ligands (Sonic hedgehog—Shh, Indian hedgehog—Ihh and Desert hedgehog—Dhh), two receptors (PTCH1, PTCH2), a key signal transducer smoothened (SMO) and three transcription factors (Gli1, Gli2, Gli3). This signaling pathway is tightly regulated and is minimally activated in adult tissue, its deregulation is a feature of multiple cancers. In this study, the author hypothesized that Hh signaling mediates a crosstalk between breast cancer cells and macrophages that dictates alternative polarization of macrophages then elicits immunosuppression and support tumorigenesis. The administration of Hh signaling inhibitor such as Vismodegib, GANT61 and 5E1 led to changes in the combination of tumor infiltrating immune cells, this was characterized by a significant reduction of immune-suppressive cells and an enhancement of cytotoxic immune cells. Given the role of TAMs in immunosuppression, the author tested the potential benefit in combination of macrophage depletion and Hh inhibitor, offer a novel therapeutic approach for interfering in tumor progression through re-configuring the immune microenvironment. Overall, this study established a novel strategy in editing the immune system and eliciting the inflammatory response. Thus, inhibiting the Hh signaling can reprogram the dysfunctional tumor immune microenvironment and reduce cancer metastasis.

References

  1. Obeid, E. et al. The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol. (2013);43(1):5–12.
  2. Jiang, J. et al. Hedgehog signaling: networking to nurture a promalignant tumor microenvironment. Mol Cancer Res. (2011);9(9):1165–1174.