Notch Signaling as a Regulator of the Tumor Immune Response: To Target or Not To Target?

Abstract

The Notch signaling pathway regulates important cellular processes involved in stem cell maintenance, proliferation, development, survival, and inflammation. These responses to Notch signaling involving both canonical and non-canonical pathways can be spatially and temporally variable and are highly cell-type dependent. Notch signaling can elicit opposite effects in regulating tumorigenicity (tumor-promoting versus tumor-suppressing function) as well as controlling immune cell responses. In various cancer types, Notch signaling elicits a “cancer stem cell (CSC)” phenotype that results in decreased proliferation, but resistance to various therapies, hence potentially contributing to cell dormancy and relapse. CSCs can reshape their niche by releasing paracrine factors and inflammatory cytokines, and the niche in return can support their quiescence and resistance to therapies as well as the immune response. Moreover, Notch signaling is one of the key regulators of hematopoiesis, immune cell differentiation, and inflammation and is implicated in various autoimmune diseases, carcinogenesis (leukemia), and tumor-induced immunosuppression. Notch can control the fate of various T cell types, including Th1, Th2, and the regulatory T cells (Tregs), and myeloid cells including macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs). Both MDSCs and Tregs play an important role in supporting tumor cells (and CSCs) and in evading the immune response. In this review, we will discuss how Notch signaling regulates multiple aspects of the tumor-promoting environment by elucidating its role in CSCs, hematopoiesis, normal immune cell differentiation, and subsequently in tumor-supporting immunogenicity.

Identification of DeleteriousNOTCHMutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

“…Secondly, tumor immunogenicity regulated by DDR pathways might be enhanced by NOTCH1 inhibition (22), possibly via the direct binding between NOTCH1 and ataxiatelengiectasia mutated (ATM) (24,25). Thirdly, in immune microenvironment, the NOTCH ligands on myeloid-derived suppressor cells (MDSCs) interact with the NOTCH receptor on tumor cells and thereby improve the CSC capacity (26), which in turn increases the expression of NOTCH ligands on MDSCs (27), constituting a positive feedback eventually resulting in immune tolerance (28). Based on these observations, we hypothesized that NOTCH mutation in NSCLC might predict the clinical benefit from immunotherapy.…”

“…Compared to docetaxel, atezolizumab monotherapy decreased the hazard of death by 33% in the NOTCH WT group (HR 0.67, 95% CI 0.55-0.80, P<0.001), 49% in the non-del-NOTCH mut group (HR 0.51, 95% CI 0.27-0.96, P=0.038), and by higher proportion as 52% in the del-NOTCH mut group (HR 0.48, 95% CI 0 28. 0.85, P=0.011).…”

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance

“…Another lncRNA, NOTCH1 associated lncRNA in T ALL (NALT), is also found to be associated with the Notch1 gene and functions as a transcription factor to activate Notch signaling and promote cell proliferation in pediatric T-ALL cells [229]. Role of Notch signaling in normal and effector immune cell differentiation is well established [230]. Furthermore, Notch can regulate various components of TME, including immune cells, fibroblasts, endothelial, and mesenchymal cells [230].…”

PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis

“…42 However, Notch2 has a positive antitumor immune-boosting effect in CD8 T-cells 43 and its expression on dendritic cells is important for their survival. 44 On the other hand, Notch3 induces regulatory T-cell generation 44 and therefore it is possible that agents able to selectively target Notch3 would be more successful in the treatment of cancer.…”