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Immunoediting takes place in three stages and helps answer some of scientists' longstanding questions — such as why some tumors re-emerge after lying dormant for years — that are rooted in the differences in the immune system's responses to cancer and infection. + Elimination phase — The first phase of immunoediting occurs when the immune system identifies and attacks the cancer cells whose antigens, chemical secretions or behaviors indicate they are threats to the system. + Equilibrium phase — In immunoediting's second phase, tumors appear to go dormant due to a balance that is established between immune control and tumor development. This balance is achieved because the cancer cells remaining after the elimination phase go through rapid division and build up mutational changes that prevent their destruction by the immune system. + Escape phase — The final phase of immunoediting occurs when tumor cells that defy recognition or elimination by the immune system manifest as growing tumors that can be seen by physicians with imaging. Changes in the cells as they react to immunoediting or immune system changes in response to the cells can initiate the escape phase. The authors of the article noted that tumor escape can be made possible when some cancer cells no longer present signals to the immune system that help the system distinguish cancer cells from normal cells. Other cancer cells may form a state of immunosuppression within the tumor, which prevents control by the immune system. Although the ways in which cancer circumvents the immune system are still being explored, its ability to do so is now accepted as one of the disease's core characteristics. Designing Effective Immunotherapies "All of the principles of infectious disease that were applied to cancer failed," Dr. Curiel says. "Only in the last seven to eight years have scientists begun to appreciate that cancer has a different rulebook. In 2004, we learned that in humans, there is an immune cell in cancer that is generated because the cancer is there. That immune cell turns your immune system off, meaning the system is now working for the cancer instead of you. All of a sudden, scientists started to think about removing the bad stuff from the immune system rather than trying to boost the immune response by transferring in other immune cells." During the last few years, a researcher posited that certain immune pathways could be turned off instead of on. Rather than bringing in more cells, it became apparent that certain "counterproductive" cells, as Dr. Curiel describes them, must be turned off to effectively fight cancer. "There must be a multifaceted approach," Dr. Curiel says. "One has to turn off regulatory T cells and bad receptors, as well as turn off the stuff that was worked on before. Once you combine those, you can put together an immune product to treat cancer. I believe we are at the very early stages of very significant immunotherapies for cancers. It is going to be a long, drawn-out affair, but now that we have the understanding of these bad cells and counterintuitive things that are going on, we have good models in the labs to study them. With that understand- ing, we can go back to the drawing board and redesign some clinical trials that I expect to produce leaps forward during the next five years. Ultimately, immunotherapy won't be the big end-all; it will be one component of a multifaceted approach that combines surgery, radiation, chemotherapy and some of these new pathway inhibitor drugs. Understanding how these pieces work together will be key to sorting out the future of cancer treatment." n MDNEWS.COM MD NEWS Central New York | 15 SHINING A LIGHT ON A DECEIVING SIGNAL HORMONE THERAPY HAS proven to be a useful tool in the treatment of certain types of breast cancer, but some tumors can become resistant to it. The recent discovery of a false signal produced by the body that thwarts hormone therapy may allow existing drugs to be used in new ways to fight stubborn tumors. In a paper published last year in the journal Cancer Research, Tyler Curiel, M.D., M.P.H., medical oncologist and immunologist at the University of Texas Health Science Center at San Antonio's Cancer Therapy & Research Center, and a colleague from the Tulane University School of Medicine discovered a fake signal that drives cancer growth even when a woman's estrogen receptor is gone and the cancer has become resistant to hormone therapy. The signal is produced by the protein CXCL12, which causes the receptor CXCR4 to stimulate the cell to act like it is receiving estrogen when it is not. Hormone therapy is unable to block the protein, which allows even estrogen receptor-less tumors to keep growing. "Estrogen-resistant, hormone-refractory breast cancers are the types that cause death because the cancer grows even without estrogen or the estrogen receptor," Dr. Curiel says. "Cells become resistant to hormone therapies when their tumors become hormone resistant. If you block the receptor, therapies become more effective. It looks like this is an immune pathway that allows cells to grow in an estrogen- independent fashion. Drugs are available right now that were designed for other purposes that can block this receptor. There are many examples of receptors that we need to learn more about — what their purpose is and whether or not turn- ing them off will help fight the tumor. I see a lot of potential to exploit these pathways."