title: Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy.
abstract: Locally produced transforming growth factor-beta (TGF-beta) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-beta suppression using the TGF-beta type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-beta (Ad.IFN-beta) was injected intratumorally once in established s.c. AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a Kras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing human papillomavirus-E7 (HPV-E7; Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine expression and cell populations were measured in tumors and spleens by real-time PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.IFN-beta increased the number of intratumoral leukocytes (including macrophages, natural killer cells, and CD8(+) cells) and increased the percentage of T cells expressing the activation marker CD25. SM16 also augmented the antitumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8(+) T cells in the spleens but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-beta signaling pathway augments the antitumor effects of Ad.IFN-beta immune-activating or Ad.E7 vaccination therapy. The addition of TGF-beta blocking agents in clinical trials of immunotherapies may increase efficacy.
authors.affiliation: Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kim
authors.forename: George
authors.initials: G
authors.lastname: Buchlis
authors.forename: Zvi G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Andrew
authors.initials: A
authors.lastname: Haas
authors.forename: Hung Kam
authors.initials: HK
authors.lastname: Cheung
authors.forename: Xiamei
authors.initials: X
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Corbley
authors.forename: Larry R
authors.initials: LR
authors.lastname: Kaiser
authors.forename: Leona
authors.initials: L
authors.lastname: Ling
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007125:Immunogenetics / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D053961:Azabicyclo Compounds; D019496:Cancer Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; C090509:Icam1 protein, mouse; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; C528106:SM16 compound; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta