Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth
© Enderling et al.; licensee BioMed Central Ltd. 2012
Received: 15 March 2012
Accepted: 16 May 2012
Published: 28 July 2012
The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression.
We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression.
A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response.
Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step “immunoediting” concept – the modulation of tumor growth through inhibition, selection and promotion.
Tumor growth dynamics are usually marked by the defining features of immunoediting; initial growth amidst productive immune response, an equilibrium state where tumor growth and suppression by immune response are more or less in balance, and malignant progression, as tumor subpopulations selected for immune resistance or evasion during the previous phase drive tumor expansion [1, 4]. The selection of tumor cells resistant to infiltrating immune cells might explain the strong correlation between number of tumor-associated macrophages and poor prognosis . The tumor-promoting effect of macrophages and the immune system in general has been attributed to second-order events such as production of angiogenic factors and matrix metalloproteinases (MMPs), because the primary cytotoxic cell killing is intuitively tumor-inhibiting . However, it has been shown recently that cell kill might paradoxically benefit tumor progression in heterogeneous tumors  and in particular, that a sufficient source for this heterogeneity may lie in the tumor-intrinsic interactions between cancer stem cell and non-stem cell fractions that give rise to a ‘self-metastatic’ phenotype [13, 14]. Here we present a model of self-metastatic tumor growth subject to immune action, and show in this setting that the basic cytotoxic function of the immune system alone can reproduce the experimentally- and clinically-observed multifaceted features of immunoediting – elimination, equilibrium, and escape.
or (ii) dependent on the tumor size in response to a growing cell population, as later described. The probability αof immune reactant-induced death for a non-stem cancer cell at position (xy) at time tis equated to the immune reactant concentration at this position at that time, i.e., α=c(xyt). In line with recent literature we assume cancer stem cells evade the immune response [6, 7, 35, 36]. A schematic of the cell dynamics and the hybrid two-layer architecture is shown in Figure 2.
Dual effect of the immune system
Cancer stem cells
Cancer stem cell ratio (%)
Self-metastastic morphology and immune selection
Early and late effects of an adaptive immune response
We presented a cellular automaton model of heterogeneous tumor growth and the impact of an induced immune response on tumor dynamics. Intrinsically, without an immune response, a heterogeneous tumor population comprised of cancer stem cells and non-stem progenitors grows as conglomerates of self-metastases [13, 14]. This morphological phenomenon results from the interplay of cell proliferation, cell migration and cell death. With increasing cell death intra-tumoral spatial inhibitions are loosened, which in turn enable cancer stem cell cycling and thus, counter-intuitively, tumor progression. Focusing only on the cytotoxic function of the immune system we were able to observe all immunoediting roles of the immune system: immune promotion at weak immune responses, immunoinhibition at strong immune responses, and immunoselection at all levels. Simulations of our model support a hypothesis previously put forward by Prehn [2, 8–10] that comparable tumor sizes can be observed for weak and strong immune reactions (either side of the peak in Figures 1and 3). Our model augments these studies by highlighting the different tumor compositions expected, including a malignant enrichment in cancer stem cells following a strong immune response. We conclude that tumors that progress to clinical presentation, particularly after strong immune responses, are likely to be heavily enriched in cancer stem cells. Moreover, when the immune system selection force is removed, the initial ratio of cancer stem cells to non-stem cells is re-established, showing that long-term cancer stem cell enrichment requires continuous dynamic maintenance. We propose more generally that a stem-cell-expansive influence may take the form of anything that encourages morphological fingering. Beyond immune response, this could include cell death, or even growth within restricted thin channels, as might be expected e.g. during invasion of host tissue.
The work of P.H. and H.E was supported by DOE-DE-SC0001434, Office of Science (Office of Biological and Environmental Research [BER]), US Department of Energy (to P.H.). The work of L.H. was supported by DOE-DE-SC0002606, Office of Science (Office of Biological and Environmental Research [BER]), US Department of Energy (to L.H.).
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