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 antitumor immunity.

• Authors: Asel K Biktasova, Duafalia F Dudimah, Roman V Uzhachenko, Kyungho Park, Anwari Akhter, Rajeswara R Arasada, Jason V Evans, Sergey V Novitskiy, Elena E Tchekneva, David P Carbone, Anil Shanker, Mikhail M Dikov
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 22 Pg. 4728-41 (Nov 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26404003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Calcium-Binding Proteins
• Dlk1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Receptors, Notch
• Recombinant Fusion Proteins
• Erlotinib Hydrochloride
• EGFR protein, mouse
• ErbB Receptors

Topics

• 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, 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)