Multivalent Forms of the Notch Ligand DLL-1 Enhance Antitumor T-cell Immunity in Lung Cancer and Improve Efficacy of EGFR-Targeted Therapy

Abstract

Activation of Notch signaling in hematopoietic cells by tumors contributes to immune escape. T cell defects in tumors can be reversed by treating tumor-bearing mice with multivalent forms of the Notch receptor ligand DLL-1, but the immunologic correlates of this effect have not been elucidated. Here we report mechanistic insights along with the efficacy of combinational treatments of multivalent DLL-1 with oncoprotein targeting drugs in preclinical mouse models of lung cancer. Systemic DLL-1 administration increased T cell infiltration into tumors and elevated numbers of CD44+CD62L+CD8+ memory T cells, while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells, enhanced expression of T-bet and phosphorylation of Stat1/2. Adoptive transfer of T cells from DLL1-treated tumor-bearing immunocompetent hosts into tumor-bearing SCID-NOD immunocompromised mice attenuated tumor growth and extended tumor-free survival in the recipients. When combined with the EGFR-targeted drug erlotinib, DLL-1 significantly improved progression-free survival by inducing robust tumor-specific T cell immunity. In tissue culture, DLL1 induced proliferation of human peripheral T cells but lacked proliferative or clonogenic effects on lung cancer cells. Our findings offer preclinical mechanistic support for the development of multivalent DLL1 to stimulate anti-tumor immunity.

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

“…Indeed, ectopic expression of NICD rendered CD8 + T-cells less susceptible to the regulatory effects of tumors and increased their efficacy upon ACT (14). Moreover, activation of T-cell-Notch through a DLL1-Fc fusion complex induced central memory CD8 + T-cells that had heightened anti-tumor effects (15,36). Accordingly, systemic DLL1 delivery promoted T-cell infiltration into tumors and enhanced efficacy of EGFR-targeted therapy (36).…”

“…Moreover, activation of T-cell-Notch through a DLL1-Fc fusion complex induced central memory CD8 + T-cells that had heightened anti-tumor effects (15,36). Accordingly, systemic DLL1 delivery promoted T-cell infiltration into tumors and enhanced efficacy of EGFR-targeted therapy (36). Collectively, these studies show that activation of DLL-Notch signaling could represent an opportunity to restore CD8 + T-cell responses in tumors.…”

Co-Expression Analysis Reveals Mechanisms Underlying the Varied Roles of NOTCH1 in NSCLC

“…Other studies have proposed that DLL1 ligand treatment results in increased Notch activity and may be beneficial by enhancing T-cell infiltration in tumors. 46 Our studies were performed using human cell lines with NOTCH1 KD that were implanted in NSG mice. These animals lack T and B cells, but the mouse innate immune system is at least partially intact.…”

Update on the Current Revolution in Cancer Immunotherapy

“…The NK cells in the proximity of activated CD8 + T cells showed functional remodeling exhibited by upregulation of effector, tissue-migratory and signaling molecules. This work suggests that tapping innate and adaptive lymphocyte teamwork in conjunction with lymphocyte-stimulatory pharmacological strategies, such as bortezomib [18] or engineered Notch ligand multivalent clusters [19], would be key to successful immunotherapy.…”