Resuscitating Cancer Immunosurveillance: Selective Stimulation of DLL1-Notch Signaling in T cells Rescues T-cell Function and Inhibits Tumor Growth

Abstract

Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immune surveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape are still incomplete. Here we report a novel mechanism of escape from T cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating vascular endothelial growth factor (VEGF). Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T cell immunity and suppress tumor growth.

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

“…Other recent studies have shown that Notch signaling can be activated by soluble forms of the ligands Jagged and Delta (19)(20)(21). The soluble Jagged and Delta have different effects on tumor progression--soluble Delta inhibits tumor growth (22,23), whereas soluble Jagged strongly aggravates the malignant progression of cancer. More specifically, Jagged plays an important role in inducing epithelial to mesenchymal transition (EMT) as well as promoting cells to acquire cancer stem cell (CSC) properties (20).…”

Targeting notch in prostate cancer—combination is the key

“…Aside from the notch-mediated responses highlighted in our Review, notch has also been implicated in: cancer immunosurveillance in both circulating tumour cells 11 and the bone marrow; 12 epigenetics; 13 and proteomic modifications. 14 Thus, the effects of the notch pathway on the development of prostate tumours, their response to treatment and cancer stem cells require extensive examination, which is further warranted by the great promise of combined antiangiogenic and antitumorigenic inhibition of the notch pathway.…”

Tuning NOTCH

“…Since the Notch system lies at a juncture of an interactive cell signaling network, activation or inhibition of selective Notch markers may serve as unique predictors of immune reconstitution, re-established tumor immunosurveillance and direct anticancer effects following cancer immunotherapy. Our work revealed that tumor and its derivative proangiogenic factors such as the Vascular Endothelial Growth Factor (VEGF) [17,18] down-regulates the expression of Delta-like Notch ligands in the hematopoietic compartment of mice as well as humans, and the resulting decrease in ligand-induced Notch activation leads to defects in T cells [16]. Paradoxically, we also recently discovered that stimulation of DLL1-mediated Notch signaling by over-expression of DLL1 in the hematopoietic compartment or by systemic administration of a prototypic therapeutic reagent, clustered multivalent DLL1, was sufficient to correct tumor-induced defects in T lymphocyte differentiation, and enhance T cell anti-tumor immunity to produce significant tumor inhibition in mouse lung cancer models [16].…”

“…Besides the established roles of the Notch system described above, our recent discovery of its significance for antitumor effector functions and memory [16] reveals important gaps in current knowledge. Since the Notch system lies at a juncture of an interactive cell signaling network, activation or inhibition of selective Notch markers may serve as unique predictors of immune reconstitution, re-established tumor immunosurveillance and direct anticancer effects following cancer immunotherapy.…”