Immunotherapy as a potentially promising approach for treatment of colorectal cancer is based on several lines of evidence. The earliest came from a landmark study in 1998 by Haruo Ohtani, M.D., who demonstrated that the presence and location of CD8+ killer T cells within the tumor microenvironment (aka “tumor-infiltrating lymphocytes,” or TILs) correlated with better outcomes in colon cancer. This study provided early evidence that immunotherapies that can induce or enhance optimal immunologic conditions within colorectal cancers may hold promise for extending the lives of colorectal cancer patients.
Studies to characterize immunological parameters that can aid prognosis have recently led to the development of a new tool, the Immunoscore, by Jérôme Galon, Ph.D., which provides a novel way of classifying tumors that works better than the current staging system in predicting rate of relapse and survival in colorectal cancer patients. The traditional tumor staging system (TNM classification) provides limited prognostic information, and does not predict response to therapy. The Immunoscore, as an addition to TNM staging, may provide an essential prognostic and potentially predictive tool that can facilitate clinical decision-making, including rational stratification of patient treatment. An international task force, involving investigators in more than 20 countries, is now under way to validate the Immunoscore, the results of which may lead to the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). A recent paper, on which CRI CEO Jill O’Donnell-Tormey, Ph.D., is a co-author, discusses these efforts in more detail. (Access the Paper)
Other studies by CRI scientists that are shedding light on the understanding and treatment of colorectal cancer include:
- Research by Dirk Jäger, M.D., a member of the CRI/Ludwig CVC Trials Network at the University of Heidelberg in Germany, is also working to elucidate how immune parameters correlate with prognosis in colorectal cancer. He has published several studies demonstrating that T cell infiltrates at the invasive margin of liver metastases from colorectal cancer predict response versus no response to chemotherapy, and represent the strongest independent prognostic factor in metastatic colorectal cancer. Jäger and colleagues are now testing how to make the tumor better accessible to the immune system by modulating the local inflammatory tumor environment.
- Chronic inflammation is a key contributor to the development of colon cancer, and several clinical and epidemiological studies have shown that patients diagnosed with inflammatory bowel diseases (IBD), such as Crohn’s disease or ulcerative colitis, have an increased incidence of colorectal cancer. Several CRI-funded investigators are exploring inflammatory pathways and how they contribute to colon cancer development. In one study, former CRI postdoctoral fellow Eran Elinav, M.D., Ph.D.,, along with former CRI predoctoral scholar Till Strowig, Ph.D., showed that deficiencies in caspase-1, an enzyme involved in the activation and maturation of inflammatory immune molecules, resulted in enhanced tumor formation in a colitis-associated colorectal cancer model. They further showed that caspase-1 plays a role in colorectal cancer development by regulating colonic cell proliferation in early stages of injury-induced tumor formation and cell death in advanced tumors, shedding new light on inflammation-initiated tumor formation, as well as offering new strategies to prevent or inhibit colon cancer development.
- Timothy Eitas, Ph.D., a CRI postdoctoral fellow at the University of North Carolina, Chapel Hill, is also exploring the role of inflammation in colorectal cancer. In his CRI-funded project, Dr. Eitas is studying a protein called NLRX1 and its role in mediating the production of inflammatory molecules called cytokines in ulcerative colitis and colitis-associated cancer. To date, Dr. Eitas’s research has shown that NLRX1 functions to protect against worse clinical outcomes in a model of colitis-associated cancer. In models lacking NLRX1, innate immune cells called macrophages produce higher levels of IL-6, a signaling molecule that has a central role in colorectal cancer development. He has also elucidated several downstream effects of IL-6 production in the progression of colitis-associated colon cancer, each of which may offer novel immunological and molecular targets for colorectal cancer treatment.
- CRI investigator Wendy Garrett, M.D., Ph.D., of the Harvard School of Public Health, Boston, MA, is studying the contributions that gut bacteria make to the development of colon cancer. She and her colleagues have made substantial progress on this front, showing for example that a bacterium called Fusobacterium nucleatum is associated with human colorectal cancer and can cause cancer in mice. They have also identified bacterial proteins that allow cancer-promoting bacteria to attach and live in tumors. Because these bacteria are found in human colon cancer and can spur colonic tumor formation in mice, they represent potential targets for colon cancer treatment and prevention.
- Cancer-testis (CT) antigens have been a focus of therapeutic vaccine approaches, but colorectal cancer and other gastrointestinal cancers very infrequently express CT antigens. CRI researchers are employing several strategies to overcome this limitation, including new approaches to try to increase expression of CT antigens in colorectal cancer. In one approach, CRI postdoctoral fellow Jeffrey Chou, M.D., Ph.D., at Fred Hutchinson Cancer Research Center, is using the chemotherapy decitabine to enhance the expression of the NY-ESO-1 antigen in colorectal cancer cells.
- April Price, Ph.D., a CRI postdoctoral fellow at the University of California, Berkeley, is working to understand how Toll-like receptors (TLR), a type of receptor that recognizes molecules that are broadly shared by pathogens, contribute to colorectal cancer. She has developed a model that will allow her to track the expression of TLRs within cells and determine whether TLR expression is modulated during inflammation, injury, and colorectal cancer. If TLRs are linked to the development of disease, then it may be possible to dampen inflammation promoted by TLRs, which would lessen the risk of developing inflammatory bowel disease and colorectal cancer.