Reversal of tumor-induced immunosuppression by TGF-beta inhibitors

Abstract

The immune system is responsible for the early detection and destruction of newly transformed malignant cells. Some transformed cells become immunologically invisible by passive avoidance of immune surveillance (i.e., when tumor cells are immunologically indistinguishable from normal cells). Other transformed cells actively secrete cytokines that effectively blind the immune system to the presence of abnormal antigens on the tumor cell surface. Transforming growth factor-beta ("TGF-beta"), which is expressed by a majority of malignant tumors, is the most potent immunosuppressor and therefore, the most likely cytokine to be responsible for the latter phenomenon. In addition to playing a key role in tumor-induced immunosuppression, TGF-beta stimulates angiogenesis. Interestingly, tumor cells eventually become refractory to TGF-beta-mediated growth arrest, either due to loss of TGF-beta receptors or due to dysregulation in TGF-beta signaling pathways. Neutralization of TGF-beta or inhibition of its production is an effective method of cancer treatment in variety of animal models. Several agents targeting TGF-beta are in the early stages of development and include anti-TGF-beta antibodies, small molecule inhibitors of TGF-beta, Smad inhibitors and antisense gene therapy. Since tumors may express more than one isoform of TGF-beta, these new drugs should target all three TGF-beta isoforms produced by human tumors. The effects of therapies targeting TGF-beta are likely to be synergistic with cytotoxic chemotherapy and immunotherapy. Reversal of TGF-beta-induced immunosuppression is a new and promising approach to cancer therapy, with potential applications in other diseases such as AIDS.