Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.

A multi-institutional study led by Memorial Sloan-Kettering Cancer Center (MSKCC) shows that patients whose colorectal cancer has spread to the liver and who received chemotherapy directly to the liver through a pump in the abdomen (an approach called Hepatic Arterial Infusion or HAI) fare better than those who received systemic (intravenously administered) chemotherapy. The study was published online in the February 27, 2006, issue of the Journal of Clinical Oncology. "This study demonstrates that HAI therapy extends survival and improves quality of life in patients with colorectal cancer that has spread to the liver," said the study's lead author Nancy E. Kemeny, M.D., medical oncologist in the Department of Medicine at MSKCC. "These positive findings are particularly important, given that metastasis to the liver occurs in 60 percent of patients with metastatic colorectal cancer, and most patients with these liver tumors eventually die of their disease." Several smaller studies have previously compared outcomes of HAI with systemic chemotherapy, but this is the first large study that had no crossover between the groups, meaning that none of the patients in the systemic group received HAI therapy. The study included 135 patients who were assigned randomly to receive either HAI or systemic chemotherapy. All of the patients underwent surgical removal of their primary tumors in the colon or rectum before beginning chemotherapy. Patients receiving HAI then underwent a surgical procedure to have a chemotherapy pump inserted into the abdomen. This procedure can sometimes be done using a minimally invasive laparoscope. Researchers found that patients receiving HAI lived longer than those receiving systemic chemotherapy, with a median survival of 24 versus 20 months. In addition, patients receiving HAI had better response rates (47% versus 24%) and longer time to disease progression in the liver (9.8 months versus 7.3 months). Patients receiving HAI did not experience the usual side effects associated with systemic therapy such as diarrhea, decreased white blood cell counts, and hair loss. However, because patients on the HAI regimen experienced mild toxicity to the liver, their liver function was monitored closely throughout the duration of treatment to prevent the toxicity from becoming more severe. The research began in 1996, before chemotherapy drugs such as irinotecan and oxaliplatin were available, so both sets of patients received the standard drugs at the time, fluorouracil and leucovorin, and had access to the newer drugs as they became available. According to Dr. Kemeny, studies are currently underway at MSKCC using HAI therapy in combination with newer drugs, and response rates appear to be even higher. Furthermore, the addition of HAI therapy is also being investigated in patients with primary liver cancer. The multi-institutional trial was conducted by researchers from the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group.