The crux of the argument provided by Qin and Blankenstein antagonising immunosurveillance of autochthonous tumours is not that immunosurveillance does not occur, but that subclinical tumours induce immune tolerance, rather than evolving through a process of immunoselection. Although current analysis of the literature falls short of resolving this controversy, it is tempting to speculate that elements of both theories may be true on a case-by-case basis for chemically induced tumours. Due to the heterogeneity of 3-MCA-induced sarcomas in immunocompetent mice, a few being rapidly progressive and the majority developing to a small size and eventually being either rejected or displaying late spontaneous outgrowth, it is highly likely that the immune response to these tumours is also heterogeneous. Rapidly progressive sarcomas may acquire an array of genetic mutations that impart a particularly aggressive phenotype capable of out-pacing an immune response in an immunocompetent animal. These rapidly progressing tumours may also never acquire particularly immunogenic mutations, and therefore remain below the threshold of immune detection. Tumours, which develop slowly in immunocompetent mice and endure a period of ‘equilibrium' with the immune system may eventually develop sufficient clonal antigenicity to engage an immune response. This immune response may then either lead to elimination of the tumour, or may be overcome by the tumour either via the induction of tolerance, the acquisition of local and/or systemic immunosuppressive elements by the tumour or by an increased proliferative capacity resulting from additional genetic mutations.
Another observation made by Koebel et al is the lag time in immunocompetent mice between the emergence of rapidly growing tumours and the times at which ‘stable' tumours emerge. There appears to be a ‘tumour-free' period of about 40 days between the rapidly growing tumours and the stable masses. It would be expected that within a given tissue, a specific chemical insult would have a predictable lag time between the insult and the average time at which tumours emerged, and that the emergence of tumours following that lag time would follow a Gaussian distribution. However, the data clearly indicate a bimodal distribution of tumour incidence with an early peak of aggressive tumours and a delayed peak of less-aggressive, immunogenic tumours. Therefore, it is possible that most mice, both immunocompetent and immunodeficient, develop tumours at equivalent time points following a given inoculation with 3-MCA, but that immunocompetent mice are capable of eliminating the majority of transformed cells at this early time point (even before a tumour nodule is palpable), which may or may not reemerge following clonal expansion and enter a period of immune equilibrium.
In contrast to chemically induced tumours, virally induced cancers result from the prolonged expression of viral proteins, many of which are highly immunogenic, and must necessarily evade immune elimination either by the induction of tolerance, the loss of immunogenicity or, as in the case of Kaposi's sarcoma, remain latent until an immunoprivileged opportunity arises (Luppi et al, 2000
; Scadden, 2003
; Kannagi, 2007
). Two impressive examples of how viruses can evolve to manipulate the immunogenicity of the cells they infect are KSHV (HHV-8) and HTLV-1. KSHV is able to establish long-term infection of the human host because of the functions of the proteins encoded by the virus. Specifically, KSHV-encoded vFLIP and vIRF-1 enable the virus to differentially regulate MHC-I transcription, allowing the virus to maintain an immune stalemate, which protects both the host and the virus from destruction (Lagos et al, 2007
). In the case of HTLV-1, the virally encoded Tax protein directs a multitude of intracellular functions promoting the survival and proliferation of infected cells, but it is also a powerful antigen in the evolution of an anti-HTLV-1 immune response; indeed, progression from chronic HTLV-1 infection to adult T-cell leukaemia often coincides with the reduced expression of the Tax protein (Kannagi, 2007
Autochthonous tumours are inherently different from virally induced tumours in that spontaneous tumours develop mutations over time, which may or may not result in the presentation of an immunogenic peptide. Gene-targeted models of spontaneous tumours have been developed recently, and have begun to illustrate the importance of innate immune surveillance and editing of emerging tumours. Using models of spontaneous prostatic adenocarcinoma and B-cell lymphoma, Guerra et al (2008)
illustrate that mice deficient in the natural-killer cell receptor, NKG2D, develop earlier and more aggressive disease than the immunocompetent mice. These authors also show that the aggressive tumours developed in NKG2D-deficient mice express higher levels of NKG2D ligands (which mediate NK-mediated destruction of some tumour cells) than the tumour cells from wild-type mice, suggesting that in immunocompetent mice one of the early events in the immunoediting of spontaneous tumours may be the selection of tumour-cell variants that express low levels of NKG2D ligands.
The hypothesis that both spontaneous and virally induced tumours can be recognised and controlled by the immune system is now clearly supported both by clinical and laboratory data (Farge, 1993
; Curtis et al, 1997
; Luppi et al, 2000
; Scadden, 2003
; Kasiske et al, 2004
; Kannagi, 2007
; Lagos et al, 2007
). Furthermore, the idea that tumour development in an immunocompetent animal proceeds through a variable sequence of immunologic checkpoints involving tolerance induction, immunoselection, immune evasion and/or immune elimination has been well supported by experimentation with 3-MCA-induced sarcomas (van den Broek et al, 1996
; Kaplan et al, 1998
; Smyth et al, 1999
; Shankaran et al, 2001
; Dunn et al, 2002
; Koebel et al, 2007
). The resolution to this controversy will likely require larger scale studies by multiple investigators using identical chemical dosing and delivery protocols, in identical strains of immunocompetent and immunodeficient mice. A major goal of these studies should be to narrow the predicted range of sarcoma formation at individual 3-MCA doses (), such that comparisons between immunocompetent and immunodeficient mice may be validated. Given the importance of tumour-specific or -associated antigens in the generation of antitumour immune responses, these studies should also be performed using a system where antigens may be defined and tracked throughout the development of spontaneous or chemically induced tumours, techniques for which have been described (Willimsky et al, 2008
). The criteria for categorising ‘tumour-free' mice must also be clarified. Furthermore, recent work with spontaneous tumour models suggests that the role of the innate immune system in controlling tumour formation may be underappreciated by chemically induced models of tumour formation (Guerra et al, 2008
), so future studies should seek to incorporate elements of both systems to fully appreciate the immune control of cancer. Even after these studies are performed, it is highly likely that some tumours will be found to induce early immune tolerance, some will develop independent of immune regulation and some will run the proposed gauntlet of immune elimination, equilibrium and eventually escape.