Targeting cell surface inhibitory receptors (checkpoint inhibitors) has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms of the regulation involved may also differ among different cancer types. In addition to checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-beta is a very potent immunosuppressive cytokine which has been shown to be involved in suppression of tumor immunity. TGF-beta has three isoforms, TGF-beta1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-beta facilitates natural tumor immunosurveillance as well as tumor vaccine efficacy. It also has been demonstrated that TGF-beta1 plays a critical role in the induction of Treg cells, IL-17-producing T cells and MDSCs. However, roles of other isotypes of TGF-beta are not well studied yet. In this study we asked whether it is necessary to inhibit TGF-beta3 to enhance tumor immunity induced by a tumor vaccine in a syngeneic TC1 tumor model. When the tumor reached at least 5 mm in diameter, the mice were given a peptide-based vaccine targeting HPV16 E7, which is an oncogene expressed in TC1 cells. Although the vaccine alone had minimal effects on tumor growth, combination with an anti-TGF-beta antibody that neutralizes all three isoforms significantly delayed tumor growth. A similar effect was obtained with an antibody that neutralizes only TGF-beta1 and 2 but not TGF-beta3. Thus, it is not necessary to block TGF-beta3 to overcome immune suppression. Flow cytometric analysis of immune cells in tumor draining lymph nodes and tumors showed that there was no difference in the number of Treg and MDSCs between mice with/without treatment. The vaccine significantly increased the number of tumor antigen-specific CD8+ T cells and IFN-gamma producing T cells in tumors. The TGF-beta inhibitor together with the vaccine increased the number of T cells infiltrating tumors two weeks after the vaccination, but not just one week after vaccination. The vaccine also induced a significant number of T-bet-expressing T cells (both CD4 and CD8) in tumors, and anti-TGF-beta, regardless of TGF-beta3 blockade, further increased the number of these cells. Together the results suggested that blockade of TGF-beta1 and 2 alone is sufficient to enhance therapeutic tumor vaccine efficacy by facilitating the induction of Th1/Tc1 type T cells. With the notion that TGF-beta3 might be beneficial for patients in some cancers, developing TGF-beta antagonists that do not inhibit TGF-beta3 may be lead to better outcomes.
Citation Format: Masaki Terabe, Faith C. Robertson, Shingo Kato, Emma De Ravin, Katharine Clark, Anja Bloom, Amer M. Mirza, Jay A. Berzofsky. Inhibition of TGF-beta1 and 2 facilitates therapeutic tumor vaccine efficacy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B137.