New perspectives on cancer & the immune system
Three CRI scientists describe immunity’s paradoxical role in the promotion and control of cancer.
In a new review article published in last week’s special issue of Science focusing on the past forty years since the U.S. declared "War on Cancer," three Cancer Research Institute scientists describe how advances in the field of tumor immunology have revealed a complex and paradoxical relationship between cancer and the immune system.
It also discusses how a growing understanding of this relationship is providing a scientific foundation for new therapies capable of unleashing the immune system’s protective powers against cancer.
Several recent breakthroughs in cancer treatment are based in immunological principles described in the review.
These include Yervoy (ipilimumab, anti-CTLA-4), a monoclonal antibody that received FDA approval today for the treatment of advanced metastatic melanoma, Provenge (sipuleucel-T), a dendritic cell vaccine that received FDA approval in April 2009 for the treatment of advanced, hormone-refractory prostate cancer, the vastly successful monoclonal antibodies Herceptin and Rituxan approved in the 1990s for the treatment of breast cancer and non-Hodgkin’s lymphoma, emerging therapeutic cancer vaccines, and new treatment strategies that combine standard chemotherapy and radiation therapy with investigational cancer immunotherapies.
The review places these treatment advances within a scientific context spanning a century of laboratory and clinical effort aimed at learning how to unleash the power of the immune system to fight cancer.
Authors Robert D. Schreiber, Ph.D., Lloyd J. Old, M.D., and Mark J. Smyth, Ph.D., at Washington University School of Medicine in St. Louis, MO, the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, NY, and the Peter MacCallum Cancer Centre and University of Melbourne in Melbourne, Australia, respectively, describe in their review how fundamental discoveries made over the past twenty years reveal that the immune system plays a dual role in protecting against cancer and in promoting cancer growth.
Taken together, these insights support a unifying conceptual framework they call "cancer immunoediting."
"The cancer immunoediting paradigm succeeds in answering a number of questions that have eluded tumor immunologists for decades, such as why some tumors in a patient respond to immunotherapy but other tumors in the same patient do not, how tumors can sometimes lie dormant in patients for years before re-emerging, and why dormant cancer cells can become active in immuno-suppressed patients receiving organ transplants from apparently healthy donors," says Schreiber.
"It also provides a platform for improving current cancer treatments and developing new therapeutic strategies that aim to interfere with or reverse phases of the immunoediting process that contribute to tumor growth."
During cancer immunoediting, the immune system is able to recognize and attack the most immunologically vulnerable cancer cells, i.e. those cancer cells that clearly appear dangerous to the immune system because they display molecular markers that identify them as damaged, secrete chemicals associated with dysfunctional cellular activity, or otherwise behave in ways the immune system recognizes to be dangerous.
Schreiber, Old, and colleagues have dubbed this first phase of cancer immunoediting the "elimination" phase.
"We hypothesize that elimination is occurring all the time in healthy hosts," says Schreiber, "where the immune system is able to destroy nascent cancerous cells before they can develop into tumors."
This process has not yet been directly observed in living animals or humans, but has been indirectly substantiated by the presence of tumor-specific immune cells and antibodies found in the blood of healthy people and animals with no evidence of cancer.
In the second phase of cancer immunoediting, called "equilibrium," surviving cancer cells continue to divide rapidly, accumulating mutational changes by chance or in response to immunological pressure that enable tumors to impair the immune system’s ability to eliminate them.
Rather, a balance between immune control and tumor growth is maintained, giving the appearance of tumor dormancy.
Over time, however, cancer cells can continue to undergo sculpting by the immune system and eventually enter into the third and final phase, "escape."
During the escape phase, tumor cells that have acquired the ability to circumvent immune recognition and/or destruction emerge as progressively growing, visible tumors. The switch from equilibrium to escape can be caused either by changes in the tumor cells in response to the immune system’s editing functions, or because the immune system changes in response to increased cancer-induced immunosuppression or immune system deterioration.
The ability of cancers to evade immune attack has recently been accepted as one of the key defining characteristics, or hallmarks, of cancer, as described in a recent paper from Hanahan and Weinberg published earlier this month in Cell.
How cancer evades the immune system is still a topic of intense research, as Schrebier, Old, and Smyth describe in their review.
"Some cancer cells stop signaling danger to the immune system through loss of the ability to process and present surface markers, called antigens, that help identify them to the immune system," says Old. Without signals that differentiate them from normal cells, these cancer cells become "invisible" to the immune system.
Another channel for tumor escape is opened when cancer cells establish an immunosuppressive state within the tumor microenvironment. "Tumor cells can begin to secrete chemicals, called cytokines, that slow or stop immune cells, or they recruit regulatory immune cells whose job in the body is to prevent activated immune cells from causing harm to self, a state called autoimmunity," Old says.
When recruited to tumor sites, regulatory cells inhibit tumor-specific immune attack. Studies of tumors infiltrated with immune cells have demonstrated a clear relationship between the ratio of regulatory cells to effector, or cell-killing, immune cells and overall patient prognosis, with those having fewer regulatory cells faring better than patients whose tumors have become more immunosuppressive.
According to the papers authors, to be effective, cancer immunotherapies will have to increase the quality or quantity of immune cells capable of eliminating cancer cells, reveal additional protective tumor antigens, and/or eliminate cancer-induced immunosuppression.
Multiple forms of immunotherapy are being explored to achieve these objectives, including therapeutic cancer vaccines, adoptive transfer of tumor-specific immune cells, monoclonal antibodies that target cancer cells for elimination, and approaches that inhibit or destroy molecular or cellular mediators of cancer-induced immunosuppression.
"Indeed, the interface between conventional approaches such as surgery, radiotherapy, standard and new small molecule targeted chemotherapies (eg.Gleevec, kinase and B-raf inhibitors) and all of these new immunotherapeutic approaches is extremely exciting. It will prove a special challenge for institutions, pharmaceutical companies, and regulatory authorities alike to rationally deliver these combinations to cancer sufferers (or patients) in a timely way," Smyth says.
The authors also point to future work in cancer immunoediting that will address questions like which components of the immune system play a role in each of the three phases of cancer immunoediting and how, what are the specific differences between tumor antigens on immunoedited cells compared to unedited tumors, is it possible to predict how a tumor will be immunoedited based on the types of antigens that are expressed, is a durable state of immune equilibrium a desirable and attainable endpoint for cancer immunotherapy, and how can we most effectively inhibit cancer-induced immunosuppression at the tumor site without inducing autoimmunity?
Finding answers to each of these important questions will provide tumor immunologists with further insights needed to optimize immunotherapies for use in treating cancer patients.
In 2007, the Schreiber, Old, and Smyth jointly received the Charles Rodolphe Brupbacher Prize for Cancer Research for their joint and complementary contributions to the field of cancer immunology and, particularly, to a better understanding of the concepts of cancer immunosurveillance and immunoediting. The three scientists also received the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic and Tumor Immunology.