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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-11, Vol.75 (22), p.4728-4741
• Main Authors: Biktasova, Asel K, Dudimah, Duafalia F, Uzhachenko, Roman V, Park, Kyungho, Akhter, Anwari, Arasada, Rajeswara R, Evans, Jason V, Novitskiy, Sergey V, Tchekneva, Elena E, Carbone, David P, Shanker, Anil, Dikov, Mikhail M
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antineoplastic Agents - pharmacology; Blotting, Western; Calcium-Binding Proteins; Cell Line, Tumor; Disease Models, Animal; ErbB Receptors - antagonists & inhibitors; Erlotinib Hydrochloride - pharmacology; Female; Flow Cytometry; Humans; Immunohistochemistry; Immunotherapy - methods; Intercellular Signaling Peptides and Proteins - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Receptors, Notch - agonists; Recombinant Fusion Proteins - pharmacology; T-Lymphocytes - immunology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-1154

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 antitumor immunity.