Cancer progression is aided by the ability of tumors to evade recognition by the immune system, and researchers have identified a mechanism by which tumors escape detection. The loss of the Type III TGF-beta receptor (TGFBR3) in tumors promotes cancer progression by altering signaling in tumor-associated immune cells.
The research team, from Duke University in Durham, North Carolina, and led by Gerard Blobe, MD, PhD, used mouse models of breast cancer and melanoma to investigate the loss of TGFBR3 expression. They found that its loss effectively dampens the host’s antitumor immune response. They had previously demonstrated that TGFBR3 is frequently downregulated as cancer progresses. This study found that losing TGFBR3 expression also enhanced the TGF-beta–dependent signaling within the tumor microenvironment. This enhanced signaling suppressed the development of tumor antigen–specific immune responses in both breast cancer and melanoma.
Losing TGFBR3 expression affected the function of local dendritic cells. Signaling of TGF-beta specific to dendritic cells was found to be critical for melanoma progression, suggesting that this pathway modulates antitumor T cell responses.
The authors suggested that inhibiting the TGF-beta signaling cascade within the tumor microenvironment could generate a more robust T cell–mediated antitumor immune response. Indeed, the study found that the antitumor immune response could be synergistically enhanced, as they demonstrated by coupling the TGFBR1 inhibitor SM16 with a HER2/NEU vaccine in a mouse model of breast cancer.
Their work supports the use of TGF-beta inhibitors to enhance the efficacy of therapies that promote immune-mediated elimination of tumor cells. They also suggested that plasma levels of the shedded extracellular domain of TGFBR1 may be effective biomarkers for selecting cancer patients for immunotherapy management. Higher plasma levels of this extracellular domain were associated with superior overall survival.
Their study was published in The Journal of Clinical Investigation (2013; doi:10.1172/JCI65745).