Abstract
Cancer immunotherapy, i.e. activation of the patient s own immune system to combat cancer, represents a treatment strategy which is being clinically tested to complement surgery, radiotherapy and chemotherapy the current cornerstones of our fight against cancer. It has become clear now, that tumors not only escape immune recognition but also actively suppress antitumor immune responses. Cancer immunotherapy therefore has to overcome several obstacles. Since the immune system has evolved to fight infections there are intrinsic mechanisms that limit the ability to react against self antigens. If however, antitumor immune responses are generated, the genetic instability of tumor cells and the immunosuppressive state of the tumor microenvironment create a second barrier that hampers immune mediated tumor eradication. In order to improve cancer immunotherapy, effective manipulation of the immune system to break self-tolerance need to be designed and approaches that counteract immunosuppressive mechanisms need to be developed.
We show that treatment with tumor-specific phage display particles leads to eradication of established mouse melanoma tumors and long-term survival. The effect is initiated by tumor associated macrophages (TAMs), which after bacteriophage encounter reverse their typical immunosuppressive state and create an environment that promotes recruitment of neutrophils and potentiates neutrophil-mediated tumor destruction. The pro-tumorigenic phenotype of prostate cancer-TAMs can be also modified using zoledronic acid (ZA). We show that ZA suppresses the expression of MMP-9 by TAMs and, in combination with IL-12, enhances their tumor-eliminating functions. Furthermore, ZA drives the proliferation and activation of gamma-delta T cells which lyse ZA-pulsed prostate cancer cells.
Finally, we developed a more clinically suitable protocol for delivery of DNA vaccines using electroporation. Reduction of electroporation pulse intervals, resulting in a 10-fold reduction of total pulse length, and application of local anesthesia do not negatively affect the vigor of antigen-specific cytotoxic T lymphocytes responses normally observed after DNA electrovaccination. This study has contributed to the identification and development of novel immunotherapeutic approaches which have a significant potential for use in cancer immunotherapy.
