Targeting transforming growth factor-β2 by antisense oligodeoxynucleotide accelerates T cell-mediated tumor rejection in a humanized mouse model of triple-negative breast cancer

Transforming growth factor-beta (TGF-beta) pathway mediates suppression of antitumor immunity and is associated with poor prognosis in triple-negative breast cancer (TNBC). In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells and subsequently analyzed the role of TGF-beta 2 in the interaction between human T cells and human tumor cells. Following reconstitution of the human immune system, inhibition of TGF-beta signaling by TGF-beta 2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-beta 2 inhibition also resulted in downregulation of peripheral Foxp3 +regulatory T cells (Treg), whereas no effect was seen in the expression of CD8 + cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-gamma and reduced levels of human IL-10 and TGF-beta 2. Moreover, TGF-beta 2 inhibition resulted in increased CD8 +T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intratumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. These results indicate that TASO potentiated T cell-mediated antitumor immunity, and it is proposed that TGF-beta 2 may be a promising target in the immunotherapeutic strategy of TNBC.

Automated summary

In this study, it was shown that inhibiting TGF-beta 2 can enhance T cell-mediated antitumor immunity and decrease the levels of regulatory T cells. These findings provide a new target for immunotherapeutic strategies in triple-negative breast cancer.