Synergistic Enhancement of CD8+ T Cell–Mediated Tumor Vaccine Efficacy by an Anti–Transforming Growth Factor-β Monoclonal Antibody

Abstract

Purpose: Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4 + and CD8 + T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti-TGF-β (1D11) and a peptide vaccine on induction of antitumor immunity, and the mechanisms accounting for synergistic efficacy. Experimental Design: The effect of combination treatment with a peptide vaccine and anti-TGF-β was examined in a subcutaneous TC1 tumor model, as well as the mechanisms of protection induced by this treatment.Results: Anti-TGF-β significantly and synergistically improved vaccine efficacy as measured by reduction in primary tumor growth, although anti-TGF-β alone had no impact. The number of tumor antigen-specific CTL with high functional avidity as measured by IFN-γ production and lytic activity was significantly increased in vaccinated mice by TGF-β neutralization. Although TGF-β is known to play a critical role in CD4 + Foxp3 + Treg cells, Treg depletion/suppression by an anti-CD25 monoclonal antibody (PC61) before tumor challenge did not enhance vaccine efficacy, and adding anti-TGF-β did not affect Treg numbers in lymph nodes or tumors or their function. Also, TGF-β neutralization had no effect on interleukin-17-producing T cells, which are induced by TGF-β and interleukin-6. Absence of type II NKT cells, which induce myeloid cells to produce TGF-β, was not sufficient to eliminate all sources of suppressive TGF-β. Finally, the synergistic protection induced by anti-TGF-β vaccine augmentation was mediated by CD8 + T cells since anti-CD8 treatment completely abrogated the effect. Conclusions: These results suggest that TGF-β blockade may be useful for enhancing cancer vaccine efficacy. (Clin Cancer Res 2009;15(21):6560-9)

Cancer Immunotherapy via Dendritic Cells

“…These include antibodies that neutralize cytokines, such as interleukin-10 (IL-10) 142 , IL-13 (REF. 143) and transforming growth factor-β (TGFβ) 144,145 . Antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) 146,147 and programmed cell death 1 ligand 1 (PDL1) [148][149][150] , which block co-inhibitory signalling of the immune checkpoint in lymphocytes represent important contributors to cancer vaccines.…”

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…Thus, TGF-b can be directly secreted by many types of tumor cells, and inhibition of TGF-b can reverse the immunosuppressive effects of the tumor microenvironment, as was demonstrated in several preclinical studies. 23,100 As IL-10 and IL-13 could also be involved in tumor-induced immunosuppression, these cytokines are considered to be promising targets for antibody-mediated blockade aimed at stimulating antitumor immune responses. 101 In addition, VEGF has been shown to downregulate the development of antitumor T-cell responses.…”

Improving cancer immunotherapy by targeting tumor-induced immune suppression

“…In a range of solid tumor preclinical models, neutralizing TGF-β mAbs alone were found not to have an antitumor effect. However, when anti-TGF-β treatment was combined with other vaccine based immunotherapies there was a significant improvement in antitumor efficacy and an enhancement in CD8 + T cell and NK cell-mediated immune responses [78][79][80]. These large molecule therapies therefore appear promising as an adjuvant to improve other tumor-specific immunotherapies.…”