Cancer Antigen Discovery Program
Cancer Immunosurveillance
The ability of the body’s immune system to identify and destroy nascent tumors, thus acting as a primary defense against cancer has been debated for many decades. Recent findings by LICR investigators now offer compelling evidence for the existence of ‘cancer immunosurveillance’, and provide the basis for the rational design of cancer vaccines.
Introduction
The theory of immunosurveillance was first proposed by Burnet and Thomas in the 1950’s but was then discounted when it couldn’t be experimentally proven. However modern technologies have allowed this theory to be investigated in both mouse and human immunological systems. These studies, conducted by a team led by LICR Affiliate Dr. Robert D. Schreiber and LICR Scientist Dr. Lloyd J. Old, proved the original hypothesis (see ‘Immunosurveillance’ in the News & Views), and extended it to incorporate the process of ‘immunoediting’, the process whereby selective pressure against a tumor cell expressing a cancer antigen causes the alteration of gene expression in that tumor cell.
Immunosurveillance in Mice
LICR investigators have used two complementary experimental approaches to establish that the immune system is intricately involved in tumor resistance in mice. First, mice that are unable to produce key components of the immune system have faster growing tumors, and are significantly more susceptible to developing tumors, for example when exposed to carcinogens. Secondly, mice that are able to produce higher levels of cytokines, proteins that are key components of the immune system, had fewer spontaneous and chemically-induced tumors, and that when these did arise, or were artificially transplanted, the tumors grew more slowly.
Immunosurveillance in Humans
Given that humans cannot be studied in the same way that mice can be studied, The principal evidence that indicates the immune system is effective at preventing cancers in humans comes from observations of patients who are, or were, profoundly and persistently immunocompromized, for example individuals with Acquired Immune Deficiency Syndrome (AIDS), or recipients of organ transplants. Many ‘immunocompromized’ cancer patients have higher incidences of a number of tumor types, including those of the lung, colon, kidney and pancreas, as well as malignant melanoma. There is no evidence that any of these particular forms of cancer are caused by infections, thus arguing for a direct effect of ‘loss of’ the immune system on the development of tumors.
Further ‘cellular’ evidence of a beneficial role of the immune system in resisting cancer is the observed correlation between increased patient survival and the presence of T cells (or tumor infiltrating lymphocytes, TIL) in a variety of tumors, for example melanoma, neuroblastoma, and breast, bladder, colon, prostate, ovary, and rectal cancers.
Immunoediting
Research conducted by LICR investigators, and others, has resulted in an extension of the immunosurveillance theory to explain how some tumors escape this detection and elimination by the immune system. The proffered theory is that of ‘immunoediting’, in which the cell make-up of the tumor is ‘sculpted’ by immunological ‘selection’; essentially cells that express cancer antigens are eliminated (by the immune system) and replaced by other cells that do not express the cancer antigen. This cancer antigen loss obviously has important implications for cancer vaccine design, as the vaccine must be able to act with enough speed and force to overcome such escape mechanisms. In order to overcome the process of immunoediting decreasing the efficacy of a cancer vaccine, LICR investigators are evaluating vaccines with multiple antigens (Vaccine Composition).
Key Publications
- G.P. Dunn, A.T. Bruce, H. Ikeda, L.J. Old, and R.D. Schreiber. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology 3(11):991-998, 2002.
- H. Ikeda, L.J. Old, and R.D. Schreiber. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Reviews 13(2):95-109, 2002.
- V. Shankaran, H. Ikeda, A.T. Bruce, J.M. White, P.E. Swanson, L.J. Old, and R.D. Schreiber. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410(6832):1107-1111, 2001.
- D.H. Kaplan, V. Shankaran, A.S. Dighe, E. Stockert, M. Aguet, L.J. Old, and R.D. Schreiber. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proceedings of the National Academy of Sciences USA 95(13):7556-7561, 1998.