The immune system has an amazing ability to seek out and destroy that which is deemed foreign, and generally leaves 'self' alone. Yet, tumour cells, thanks to accumulated mutations and altered patterns of gene expression, differ from their normal counterparts. Could the same killing power that eradicates infection be harnessed to destroy cancer cells — cells that are nevertheless self?
Paul Ehrlich thought so. In 1909, he suggested that, thanks to the immune system, tumour development was usually suppressed.
Yet, attempts to target tumours by immunotherapy have been less successful than the Ehrlich hypothesis might predict. Richmond Prehn and Joan Main, in 1957, showed that tumours induced by chemical carcinogens in mice could stimulate tumour-specific responses that were able to reject those same tumours on challenge. They concluded that tumour immunity was induced by antigens unique to the chemically-induced tumour, but found that spontaneously arising tumours were not rejected when tested in the same experimental manner.
From these and subsequent studies arose the belief, summarized by Harold Hewitt and colleagues, that naturally arising tumours were not immunogenic. Moreover, Osias Stutman had reported in 1974 that athymic mice do not have an increased frequency of tumours induced by a chemical carcinogen, implying that the concept of immune surveillance providing protective immunity was incorrect. Yet, in 1982, enthusiasm for tumour immunology was rekindled by the landmark discovery by Aline van Pel and Thierry Boon that specific immunity to spontaneous tumours could be induced by vaccinating mice with mutagenized tumour cells. Their study showed that spontaneous tumours were not inherently deficient in tumour antigens, but instead failed to stimulate an effective immune response. This failure could be overcome by vaccination, a strategy that has since been adopted in numerous clinical trials.
In a technical feat by Pierre van der Bruggen and colleagues, the Boon group later reported the first identification of a tumour-specific antigen recognized by cytolytic T cells in humans, reinforcing the idea that tumour antigens can elicit a detectable tumour-specific response. Whether that response can induce, or be manipulated to induce, rejection of the tumour remains unclear. Yet Robert Schreiber and co-workers, in 2001, prompted renewed interest in immunosurveillance, showing that immunodeficient mice are more susceptible to chemically-induced, as well as spontaneous, tumours. This proves to be a 'catch 22', however, for the immunocompetent mouse: in recognizing cancer, the immune system exerts a selection pressure on a tumour cell or immunoediting, resulting in its decreased immunogenicity and eventual escape from immune-mediated eradication. More recently, Gerald Willimsky and Thomas Blankenstein suggested that sporadic tumours in mice do not lose immunogenicity, but rather induce tolerance to evade immune detection. How either model relates to tumour growth in humans remains to be determined.
While the suggestion by Ehrlich that the immune system restricts the growth of most tumours might have been optimistic, the findings that immune cells do recognize tumours have nonetheless catalysed an upswing of enthusiasm in the field of tumour immunology, and offer encouragement for immunotherapy approaches as a potential adjunct to present cancer therapy.
and lymphocytes prevent primary tumour development and shape tumour immunogenicity
