Abstract
Cancer immunotherapy, which stimulates or augments host immune responses to treat malignancies, is the latest development in the rapidly advancing field of cancer immunology. The basic principles of immunotherapies are either to enhance the functions of specific components of the immune system or to neutralize immune-suppressive signals produced by cancer cells or tumor microenvironment cells. When successful, these approaches translate into long-term survival for patients. However, durable responses are only seen in a subset of patients and so far, only in some cancer types. As for other cancer treatments, resistance to immunotherapy can also develop. Numerous research groups are trying to understand why immunotherapy is effective in some patients but not others and to develop strategies to enhance the effectiveness of immunotherapy. The Notch signaling pathway is involved in many aspects of tumor biology, from angiogenesis to cancer stem cell maintenance to tumor immunity. The role of Notch in the development and modulation of the immune response is complex, involving an intricate crosstalk between antigen-presenting cells, T-cell subpopulations, cancer cells, and other components of the tumor microenvironment. Elegant studies have shown that Notch is a central mediator of tumor-induced T-cell anergy and that activation of Notch1 in CD8 T-cells enhances cancer immunotherapy. Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells, altered dendritic cells, and tumor-associated macrophages along with regulatory T cells, are major obstacles to the development of successful cancer immunotherapies. In this article, we focus on the roles of Notch signaling in modulating tumor-infiltrating myeloid cells and discuss implications for therapeutic strategies that modulate Notch signaling to enhance cancer immunotherapy.
Highlights
Notch signaling, an evolutionarily conserved cell-fate-determination pathway, mediates close contact interactions between neighboring cells
Notch intracellular domain (NICD) translocate into the nucleus and complexes with the CSL (CBF-1/ Suppressor of Hairless/LAG-1, known as RBP-J), and mastermind-like (MAML1-3) coactivator and other proteins to form the Notch transcriptional complex, which regulates the transcription of multiple genes [2, 4, 5, 7]
Multiple soluble factors released by the tumor microenvironment perturb the normal myeloid development resulting in the accumulation of myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with immune-suppressive properties
Summary
An evolutionarily conserved cell-fate-determination pathway, mediates close contact interactions between neighboring cells. In some cases, ligand-independent receptor activation [6] triggers separation of the extracellular receptor subunit from the transmembrane subunit The latter undergoes a multistep proteolytic process, which results in the release of a Notch intracellular domain (NICD) [7]. Context-dependent Notch signaling regulates many cell fate choices and Notch dysregulation contributes to the development of various malignancies [5]. Multiple soluble factors released by the tumor microenvironment (both tumor cells and tumor-associated stromal cells) perturb the normal myeloid development resulting in the accumulation of myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with immune-suppressive properties. We will discuss the role of Notch signaling in myeloid cells (MDSC, DC, and macrophages) as a modulator of tumor immune response
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