NOTCH Signaling in T-Cell-Mediated Anti-Tumor Immunity and T-Cell-Based Immunotherapies

Abstract

The NOTCH (1-4) family of receptors are highly conserved and are critical in regulating many developmental processes and in the maintenance of tissue homeostasis. Our laboratory and numerous others have demonstrated that aberrant NOTCH signaling is oncogenic in several different cancer types. Conversely, there is also evidence that NOTCH can also function as a tumor suppressor. In addition to playing an essential role in tumor development, NOTCH receptors regulate T-cell development, maintenance, and activation. Recent studies have determined that NOTCH signaling is required for optimal T-cell-mediated anti-tumor immunity. Consequently, tumor cells and the tumor microenvironment have acquired mechanisms to suppress NOTCH signaling to evade T-cell-mediated killing. Tumor-mediated suppression of NOTCH signaling in T-cells can be overcome by systemic administration of NOTCH agonistic antibodies and ligands or proteasome inhibitors, resulting in sustained NOTCH signaling and T-cell activation. In addition, NOTCH receptors and ligands are being utilized to improve the generation and specificity of T-cells for adoptive transplant immunotherapies. In this review, we will summarize the role(s) of NOTCH signaling in T-cell anti-tumor immunity as well as TCR-and chimeric antigen receptor-based immunotherapies.

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

“…Similarly, a conditional knockout of NOTCH2 in CD8+ T cells showed that Notch 2 signalling is required for generating potent antitumour cytotoxic T cells [ 114 ]. Moreover, conditional deletion of Notch or pharmacological inhibition of Notch signalling diminishes the production of cytotoxic T cell effector molecules [ 113 , 115 , 116 , 117 ]. Naive T cells express full-length Notch receptors; however, T cells isolated from tumour-bearing mice have decreased expression of Notches 1–4 and a reduction in Notch target genes ( Deltex1, Hey1 and Hes1 ) together suggesting T cells from tumours have repressed Notch signalling and decreased effector function [ 117 , 118 , 119 ].…”

“…Moreover, conditional deletion of Notch or pharmacological inhibition of Notch signalling diminishes the production of cytotoxic T cell effector molecules [ 113 , 115 , 116 , 117 ]. Naive T cells express full-length Notch receptors; however, T cells isolated from tumour-bearing mice have decreased expression of Notches 1–4 and a reduction in Notch target genes ( Deltex1, Hey1 and Hes1 ) together suggesting T cells from tumours have repressed Notch signalling and decreased effector function [ 117 , 118 , 119 ]. This may be due to the recruitment of myeloid-derived suppressor cells (MDSC) to the tumour, which, in turn, block the expression of Notch in T cells [ 118 ].…”

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“…Similarly, the Notch pathway plays an important role in differentiation of other types of myeloid cells and probably all subsets of CD4 + and CD8 + T cells [83]. Different Notch receptors and their interaction with different ligands contribute to these processes [84]. Moreover, non-canonical Notch signaling is implicated in regulation of immune cells [85].…”

“…T helper 1 cells, cytotoxic CD8 + T cells, and M1 macrophages) supports induction of immune reactions including anti-tumor immunity, in other cells (particularly regulatory T cells) it leads to immunosuppression [86]. Thus, immunostimulatory effect of Notch signaling is often inhibited in tumor microenvironment to enable the tumor cells to escape from the host immunity [84]. Therapeutics affecting Notch signaling in malignant diseases are being developed and tested in clinical trials but their effects on immune reactions and possible combination with immunotherapy have not been properly studied.…”

“…The human IgG1 PAN-622 recognizes the catalytic domain of ASPH. This antibody is not directly cytotoxic for tumor cells but is internalized and can deliver cytotoxic moieties into cells [84]. In the subsequent study with a mouse model of metastatic breast cancer, PAN-622 was used for bioimaging and radioimmunotherapy with promising results [104].…”