1
Cornelis J.M. Melief
The immune system controls the emergence of many tumours. It now appears that this can include maintenance of dormancy/ equilibrium of small inert lesions, which grow out to become overt tumours only after suppression of immunity
Cancer is considered a fatal disease and current belief is that tumour cells need to be eradicated as quickly as possible in order to halt tumour progression and eventual death. The startling results of Koebel et al.
1 (page……) show that this needs not be the case. These authors now show in mice that induction of cancer by methylcholanthrene(MCA), a tar component of the kind found in cigarette smoke, causes an initial wave of deadly tumours affecting many animals, after which the surviving mice show no evidence of growing tumours. Deceptively, however, in these apparently healthy mice, dormant tumours still exist, which are kept in check by the immune system. This state of equilibrium can be fatally disrupted by immunosuppression, allowing the dormant tumours to wrest themselves from the tight grip of immune control, to grow out and kill their host. For the first time this work actually visualizes the small inert lesions in the dormant equilibrium state, a first step towards better characterization of tumour latency.
The concept of tumour dormancy has a long history and is welldocumented in animal models and in anecdotal clinical observations 2-5 . Also, it has long been suspected that immuno-supression can cause the outgrowth of dormant tumours. For example, the cancer malignant melanoma was observed to develop in a recipient of a kidney transplant from a donor treated for melanoma 16 years earlier and considered cured 6.
The cancer in the recipient was found to be of donor origin. Apparently the immunosupression needed for kidney graft acceptance triggered the outgrowth of the cancer that had been kept under immune control in the kidney donor for all those years. In none of the previous reports, however, the dormant state was actually visualized, nor was it documented which component of the immune system was involved in the maintenance of

2 dormancy. The current report 1 makes a big stride forward by documenting both aspects of dormancy. First, after the initial wave of MCA-induced deadly tumours, dormant tumours in immuno-competent mice only developed into progressive tumours after treatment with monoclonal antibodies depleting T-lymphocytes (T-cells) or neutralizing the action of the cytokines Interleukin-12 or interferon-y. Depletion of more broadly acting, but less specific “Natural Killer” cells had no effect. This clearly points at highly specific adaptive T-cell immunity as the component of the immune system that maintains dormancy/equilibrium. Interestingly, in a different tumour model, immunization with tumour cells can generate antibodies, that also contribute to dormancy 4 . Second, by morphology, many cells in dormant lesions showed features of cancer cells, including large cells with variable degrees of atypia, enlarged nuclei and prominent nuclear bodies, all reminiscent of the histology of progressively growing primary
MCA-induced cancers 1 . Stable masses, like growing MCA cancers, showed infiltration by immune cells, including T-cells. However, dormant lesions showed a much lower percentage of proliferating cells, but increased cell death, compared to growing sarcomas. Transient culture of cells from dormant lesions yielded atypical fibroblast-like cells that grew out as tumours upon injection into immuno-deficient, but not immuno-competent mice. In contrast, occasional tumours escaping from dormancy grew out in a high percentage of cases in immunocompetent animals.
Thus, this work for the first time characterizes a state of tumour dormancy/ latency, the hallmarks of which are stable lesions of transformed immunogenic cells and control by the adaptive immune system in a state dubbed equilibrium, because of its dynamic nature. Obviously this is a precarious situation, because either loss of immuno-competence or loss of immunogenicity can lead to tumour outgrowth as shown by the authors.
The implications of this work are far-reaching. First and foremost, the actual description and visualization of dormant lesions offers an opportunity to characterize their molecular signature as determined by gene expression profile, in comparison with growing immunogenic cancers which, in contrast to these stable lesions, fail to be controlled in immuno-competent hosts 1 .
Indeed, such understanding may lead to the development of novel therapeutic interventions, acting in conjunction with immune responses, to harness overt cancers into less aggressive stable lesions. Second, as suggested by Koebel et al.
1 , immunotherapy of cancer need not only be aimed at complete tumour eradication, but also at establishing tumour equilibrium by robust enhancement of interferon-y producing tumourspecific T-cells. Indeed, even spontaneous T-cell infiltration into human

3 cancers is now increasingly recognized as a favourable prognostic sign, independent of other prognostic indicators 6-8 .
Third, this dormancy model offers a striking parallel with chronic infections such as by M.Tuberculosis, one of the worlds most successful pathogens . M. Tuberculosis infection typically establishes asymptomatic or latent infection, which can last for decades, before the pathogen reactivates and clinical TB-disease ensues, often coinciding with a phase of immune suppression 9a,b . Indeed
M.Tuberculosisis is thought to utilize special bacterial gene products to maintain latency and it is tempting to speculate that dormant tumours use similar tricks to avoid being eradicated altogether. After all, many microorganisms utilize genes resembling genes of the host they infect. Fourth, a more intense search for dormant tumours is warranted, particularly in tumours induced by chemicals, such as those in cigarette smokers, since the current mouse system is a model for such human cancers. Obviously, dormant tumours in smokers would pose a threat and waiting for overt cancers in smokers is a notorious case of coming too late for effective therapy 10 . It may be difficult to detect truly dormant lung cancers, however, although one third of breast cancer patients, 7-22 years after mastectomy, reportedly have evidence of circulating “tumour” cells without any evidence of disease 3 . Are these cells also kept in check by immune responses or are they controlled by other mechanisms? Finally, a downside of treating cancer patients with immunosuppressive chemotherapy or irradiation may be that dormant tumour cells take the opportunity to escape from immune control.
Cornelis J.M. Melief is in the department of Immunohematology and Blood
Transfusion, Leiden University Medical Center, Albinusdreef 2, PO Box
9600, 2300 RC Leiden, The Netherlands. e-mail:c.melief@lumc.nl
1 Koebel, C.M. et al. Nature ........
2 Allan, A.L. et al. Breast Disease 26 , 87-98, (2007)
3 Vessella, R.L
. et. al. Cancer Biology & Therapy 6, 1-9, (2007)
4 Uhr, J.W. & Marches, R. Cancer Biology 11, 277-283, (2001)
5 Mackie R.M. et al. New Engl.J.Med. 348, 567-568, (2003)
6 Galon, J. et al. Science 313, 1960-1964, (2006)
7 Sato, E. et al. Proc. Natl Acad. Sci USA 102, 18538-18543, (2005)
8 Piersma S. et al. Cancer Res. 67, 354-361, (2007)
9 a)Andersen P. Trends in Microbiol. 15, 7-13, (2006); b)Leyten et al.
Microbes Infect.
8, 2052-2060, (2006)
10 Bianchi F. J.Clin.Invest. 117, 3436-3444 (2007)