title: 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.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Asel K
authors.initials: AK
authors.lastname: Biktasova
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee.
authors.forename: Duafalia F
authors.initials: DF
authors.lastname: Dudimah
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee.
authors.forename: Roman V
authors.initials: RV
authors.lastname: Uzhachenko
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Park
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Anwari
authors.initials: A
authors.lastname: Akhter
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Rajeswara R
authors.initials: RR
authors.lastname: Arasada
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Jason V
authors.initials: JV
authors.lastname: Evans
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Tchekneva
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio.
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. ashanker@mmc.edu Mikhail.Dikov@OSUMC.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio. ashanker@mmc.edu Mikhail.Dikov@OSUMC.edu.
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051880:Receptors, Notch / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors