Systemic blockade of transforming growth factor-β signaling augments the efficacy of immunogene therapy

Samuel Kim, George Buchlis, Zvi G. Fridlender, Jing Sun, Veena Kapoor, Guanjun Cheng, Andrew Haas, Kam Cheung Hung, Xiamei Zhang, Michael Corbley, Larry R. Kaiser, Leona Ling, Steven M. Albelda

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Locally produced transforming growth factor-β (TGF-β) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-β (Ad.IFN-β) 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-β 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-β signaling pathway augments the antitumor effects of Ad.IFN-β immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy.

Original languageAmerican English
Pages (from-to)10247-10256
Number of pages10
JournalCancer Research
Volume68
Issue number24
DOIs
StatePublished - 15 Dec 2008
Externally publishedYes

Fingerprint

Dive into the research topics of 'Systemic blockade of transforming growth factor-β signaling augments the efficacy of immunogene therapy'. Together they form a unique fingerprint.

Cite this