Blockade of only TGF-b1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy
Masaki Terabe1*, Faith C. Robertson1, Katharine Clark1, Emma De Ravin1, Anja Bloom1,
David J. Venzon2, Shingo Kato1, Amer Mirza3, Jay A. Berzofsky1
1Vaccine Branch and 2Data Management Section, National Cancer Institute, Bethesda, MD, USA; 3Xoma Corporation, Berkeley, CA, USA
Immunotherapy, especially checkpoint blockade, is now recognized as an established modality of cancer treatment. However, only a fraction of patients responds to current immunotherapies because of diversity of immune regulation mechanisms in cancer patients. Thus, new targets for therapy must be found. In this study, we examined TGF-b as a target of immunotherapy combined with a therapeutic vaccine. TGF-b is a potent immunosuppressive cytokine that consists of three isoforms. Previous studies demonstrated that blockade of all isoforms of TGF-b potentiated cancer vaccines. However, pan-inhibition may not be necessary, and as a recent clinical study in breast cancer reported a positive correlation between TGF-b3 abundance and better prognosis, more selective TGF-b targeting may be beneficial. Here, by using monoclonal antibodies specific for TGF-b isoforms, we asked whether it is necessary to block TGF-b3 to enhance tumor immunity in a syngeneic TC1 tumor model. In this model, protection was mediated by CD8 T cells. We found that blockade of TGF-b1 and 2 and of all isoforms had similar effects on vaccine efficacy. Both combination treatments induced a higher frequency of IFN-g producing cells among CD4 T cells and tumor antigen-specific CD8 T cells in tumor draining lymph nodes although the number of tumor antigen-specific CD8 T cells did not change. Anti-TGF-b combined with the vaccine also increased the frequency of T-bet expressing CD8 and CD4 T cells in tumors. Vaccine efficacy was further increased when combined with anti-PD-1. Altogether, these results suggest that TGF-b blockade enhances quality of vaccine-induced immune responses, promoting Th1 phenotype cells. Furthermore, blockade of TGF-b1 and 2 is sufficient to enhance therapeutic vaccine efficacy.