Dartmouth Researchers Reprogram Tumor's Cells to Attack Itself
February 03, 2015
Inserting a specific strain of bacteria into the microenvironment of aggressive ovarian cancer transforms the behavior of tumor cells from suppression to immunostimulation, researchers at Norris Cotton Cancer Center and the Geisel School of Medicine at Dartmouth have found. The findings, published in OncoImmunology, demonstrate a new approach in immunotherapy that can be applied in a variety of cancer types.
"By introducing an attenuated and safe form of the bacteria Listeria monocytogenes (Lm), in collaboration with Aduro Biotech Inc., we found that the attenuated bacteria is taken up by the immunosuppressive cells and transforms them from cells that protect the tumor into cells that attack the tumor," said Steve Fiering, PhD, lead author of the study.
Tumors protect themselves from attack by the immune system by generating an immunosuppressive microenvironment. The study's results found that Lm has a significant impact in increasing the amount of pro-inflammatory cytokines and chemokines, and recruiting immune effector cell subsets, that strongly support anti-tumor immunity. Modifying the immunosuppressive tumor microenvironment remains an approach that can be combined with other immune-based treatment to treat other cancers in addition to ovarian cancer.
"Modulation of the tumor microenvironment to make the immunosuppressive phagocytes into cells that support anti-tumor immune responses has roots in experiments done a hundred years ago by Dr. William Coley," Fiering said. "Now that we can engineer microorganisms to make them safe to use and also can track the anti-tumor immune response in great detail, it has new potential for use in cancer treatment."
The attenuated strain of Lm, developed by Aduro Biotech Inc., is already in clinical trials for the treatment of pancreatic cancer. "Our studies provide further understanding of the mechanisms involved and how this approach can be used in cancer treatment, and will support future clinical trials for treatment of ovarian cancer," Fiering said.
Co-authors on the study are Patrick H. Lizotte, BS, Jason R. Baird PhD, Cynthia A. Stevens MS, and William R. Green PhD of the Geisel School of Medicine at Dartmouth, and Peter Lauer PhD and Dirk G. Brockstedy Phd of Aduro Biotech, Inc. Funding was provided by Dartmouth Immunobiology of Myeloid and Lymphoid Cells NIH Training Grant 5T32AI007363-22 (P.H.L.); Dartmouth Center of Nanotechnology Excellence NIH 1 U54 CA151662 (S.F.); Center for Molecular, Cellular, and Translational Immunological Research NIGMS 1P30RR032136-01 (S.F.); Norris Cotton Cancer Support Grant P30 CA023108 (S.F.).Technical support was provided by Transgenic and Genetic Construct Shared Resource and by Dartlab Shared Resource with support from Norris Cotton Cancer Center.
About Norris Cotton Cancer Center at Dartmouth-Hitchcock
Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.