An insight into tumor dormancy equilibrium via the analysis of its domain of attraction

The trajectories of the dynamic system which regulates the competition between the populations of malignant cells and immune cells may tend to an asymptotically stable equilibrium in which the sizes of these populations do not vary, which is called tumor dormancy. Especially for lower steady-state sizes of the population of malignant cells, this equilibrium represents a desirable clinical condition since the tumor growth is blocked. In this context, it is of mandatory importance to analyze the robustness of this clinical favorable state of health in the face of perturbations. To this end, the paper presents an optimization technique to determine whether an assigned rectangular region, which surrounds an asymptotically stable equilibrium point of a quadratic systems, is included into the domain of attraction of the equilibrium itself. The biological relevance of the application of this technique to the analysis of tumor growth dynamics is shown on the basis of a recent quadratic model of the tumor–immune system competition dynamics. Indeed the application of the proposed methodology allows to ensure that a given safety region, determined on the basis of clinical considerations, belongs to the domain of attraction of the tumor blocked equilibrium; therefore for the set of perturbed initial conditions which belong to such region, the convergence to the healthy steady state is guaranteed. The proposed methodology can also provide an optimal strategy for cancer treatment.     

The Price equation framework to study disease within-host evolution

The evolution of infectious diseases is known to affect epidemiological dynamics, but, for some viruses and bacteria, this evolution also takes place inside a host during the course of an infection. I develop an original approach to study intrahost evolutionary dynamics of quantitative disease traits. This approach can be expressed mathematically using the ‘Price equation’ framework recently developed in evolutionary epidemiology. This framework combines population genetics and within-host population dynamics models to identify trade-offs that affect disease intrahost evolution and to predict short-term evolutionary dynamics of life-history traits. I show that this can be applied to study the evolution of viruses competing for host cells or to study the coevolution between parasites and the immune system of the host. This framework can also easily incorporate experimental data. Studying intrahost evolutionary dynamics provides insight at the within-host level, because it allows us to better understand the course of chronic infections, and at the epidemiological level, because it helps to study multi-scale evolutionary processes. This framework can be used to address important biological issues, from immune escape to disease evolutionary response to treatments.     

Modeling immunotherapy of the tumor – immune interaction

 A number of lines of evidence suggest that immunotherapy with the cytokine interleukin-2 (IL-2) may boost the immune system to fight tumors. CD4⁺ T cells, the cells that orchestrate the immune response, use these cytokines as signaling mechanisms for immune-response stimulation as well as lymphocyte stimulation, growth, and differentiation. Because tumor cells begin as ‘self’, the immune system may not respond in an effective way to eradicate them. Adoptive cellular immunotherapy can potentially restore or enhance these effects. We illustrate through mathematical modeling the dynamics between tumor cells, immune-effector cells, and IL-2. These efforts are able to explain both short tumor oscillations in tumor sizes as well as long-term tumor relapse. We then explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. Received: 22 October 1997 / Revised version: 27 November 1997     

Investigation of the mechanism and the effect of cryoimmunology in the Copenhagen rat

This study examined the potential for "cryoimmunology" to increase the destruction of the Dunning AT-1 prostate tumor after cryosurgery. Two possible mechanisms explaining the cryoimmunologic response were studied. The first was that an antitumor antibody is produced after cryosurgery. The second was that freezing induces an immunostimulatory signal that creates a T-cell response to the tumor. Six groups of animals (three experimental groups and three control groups) were treated once per week for 4 weeks with different therapies designed to investigate these mechanisms. Three types of immune response were measured: (1) the anti-AT-1 tumor immune titer (Ab response) by serum ELISA, (2) the effect on secondary tumor growth after challenge with live AT-1 cells (size and weight of the secondary tumor over time), and (3) the nature of the immunologic infiltrate into the secondary tumors by immunoperoxidase stain. ELISA showed that immune titers were present in the experimental groups after therapy, but the presence of an immune titer did not have a significant effect on tumor propagation. Histology showed the immunologic infiltrate was similar in all groups. These results showed that an immune response to AT-1 tumor was measurable by serum antibody, but it did not significantly limit secondary tumor growth or affect tumor histology. This suggests that the growth of AT-1 tumors is not inhibited by a cryoimmunological response. Thus, the effect of in vivo cryosurgery in the AT-1 tumor system would likely be limited to cellular and vascular changes.     

Immunogenic cell death-inducing metal complexes: From the benchtop to the clinic

The immune system presents a complex array of processes designed to maintain homeostasis in malignant cellular growth. Malignancy is the result of a breakdown in immune surveillance by cancer cells evading immune recognition. Significant efforts have been made in modulating immune checkpoint signaling cascades to bypass the resulting immune evasion and establish an anticancer effect. More recently, it was discovered that a form of regulated cell death can involve the stimulation of immune response as its downstream effect and subsequently re-establish immune surveillance. This mechanism, known as immunogenic cell death (ICD), is being exploited as a target to prevent tumor relapse and prevent cancer metastasis. It is now appreciated that metal-based compounds play a key role in ICD activation due to their unique biochemical properties and interactions within cancer cells. With fewer than 1% of known anticancer agents documented as ICD inducers, recent efforts have been made to identify novel entities capable of stimulating a more potent anticancer immune response. While the recent reviews by us or others focus primarily on either discussing the chemical library of ICD inducers or intricate detailing of biological pathways associated with ICD, this review aims to bridge these two topics as a concise summary. Furthermore, early clinical evidence and future directions of ICD are briefly summarized.     

Immunostimulation and Immunoinhibition of Premalignant Lesions

Background

The immune reaction may be either stimulatory or inhibitory to tumor growth, depending upon the local ratio of immune reactants to tumor cells.

Hypothesis

A tumor-stimulatory immune response may be essential for survival of a neoplasm in vivo and for the biological progression from a premalignant lesion to a malignancy. Neither a positive nor a negative correlation between the magnitude of an immune-cell infiltrate and a cancer's prognosis can reveal whether the infiltrate was stimulating or inhibiting to the tumor's growth unless the position on the nonlinear curve that relates tumor growth to the magnitude of the immune reaction is known.

Discussion

This hypothesis is discussed in relation to the development of human malignant melanomas and colorectal cancers.     

A survey of some formal models in tumor immunology

Summary Computer technology has acquired an important role in structuring a variety of biological systems. The availability of modern powerful computers has stimulated the development of good and accurate models of biological systems. Biological systems, such as the immune response against cancer, are complex and it is difficult to experimentally control all the interacting elements constituting the immune response of a host to cancer. Complex biosystems do not always behave or act as expected during experimental investigation. In these cases computer models can be helpful in understanding the behavior of such complex systems.The purpose of this review is to consider the use of mathematical models to study the immune response against cancer. The logic and design of some operable models relevant for tumor immunology will be discussed. Special attention is given to the conceptualization of a model based upon a new hypothesis of tumor rejection presented by De Weger et al. [10].Technical details concerning the mathematical aspects, differential equations, details on harware and software package etc. are not included in this survey. These details are contained to in the original papers.     

Is an immune reaction required for malignant transformation and cancer growth?

Increasing evidence has shown that probably all malignant mouse cells, even those of spontaneous sporadic cancers, are endowed with tumor-specific antigens. Stimulation of cancer growth, rather than inhibition by the immune reaction, is seemingly the prevalent effect in the animal of origin (the autochthonous animal). Small initial dosages of even strong tumor antigens tend to produce stimulatory immune reactions rather than tumor inhibition in any animal. Thus, an immune response at a low level may be an essential growth-driving feature of nascent cancers, and this may be why all cancers apparently have tumor-specific antigens. Inasmuch as a low level of immunity is stimulatory to tumor growth while larger dosages are inhibitory, immuno-selection via this low response may tend to keep the antitumor immune reaction weak and at a nearly maximal stimulatory level throughout most of a tumor's existence. These facts suggest that both suppression of tumor immunity and a heightened immune reaction might each be therapeutic although very contrasting modalities.     

Synergistic and antagonistic interaction between different branches of the immune system is related to melanin‐based coloration in nestling tawny owls

When exposed to parasites, hosts often mount energetically expensive immune responses, and this may alter resource allocation between competing life history traits including other components of the immune system. Here, we investigated whether a humoral immune challenge towards a vaccine reduces or enhances the cutaneous immune responses towards an injection of lipopolysaccharid (LPS, innate immunity) and phytohaemagglutinin (PHA, T‐cell immunity) in nestling tawny owls in interaction with the degree of plumage melanin‐based coloration. The humoral immune challenge enhanced the response to LPS similarly in differently coloured nestlings. In contrast, the same humoral immune challenge enhanced immune response to PHA in dark reddish melanic nestlings while reducing it in pale reddish melanic nestlings. Our results highlight that both antagonistic and synergistic interactions can take place among branches of immune system, and that the sign and magnitude of these interactions can vary with immune responses involved and the degree of melanin‐based coloration.     

Tumors and the danger model

This article reviews the evidence for the danger model in the context of immune response to tumors and the insufficiency of the immune system to eliminate tumor growth. Despite their potential immunogenicity tumors do not induce significant immune responses which could destroy malignant cells. According to the danger model, the immune surveillance system fails to detect tumor antigens because transformed cells do not send any danger signals which could activate dendritic cells and initiate an immune response. Instead, tumor cells or antigen presenting cells turn off the responding T cells and induce tolerance. The studies reviewed herein based on model tumor antigens, recombinant viral vectors and detection of tumor specific T cells by MHC/peptide tetramers underscore the critical role of tumor antigen presentation and the context in which it occurs. They indicate that antigen presentation only by activated but not by cancer or resting dendritic cells is necessary for the induction of immune responses to tumor antigens. It becomes apparent that the inability of dendritic cells to become activated provides a biological niche for tumor escape from immune destruction and seems to be a principal mechanism for the failure of tumor immune surveillance.     

Positive feedback and angiogenesis in tumor growth control

In vivo tumor growth data from experiments performed in our laboratory suggest that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic signals emerging from an up-regulated genetic message in the proliferating rim of a solid tumor in response to tumor-wide hypoxia. If these signals are generated in response to unfavorable environmental conditions, i.e. a decrease in oxygen tension, then the tumor may play an active role in manipulating its own environment. We have idealized this type of adaptive behavior in our mathematical model via a parameter which represents the carrying capacity of the host for the tumor. If that model parameter is held constant, then environmental control is limited to tumor shape and mitogenic signal processing. However, if we assume that the response of the local stroma to these signals is an increase in the host's ability to support an ever larger tumor, then our models describe a positive feedback control system. In this paper, we generalize our previous results to a model including a carrying capacity which depends on the size of the proliferating compartment in the tumor. Specific functional forms for the carrying capacity are discussed. Stability criteria of the system and steady state conditions for these candidate functions are analyzed. The dynamics needed to generate stable tumor growth, including countervailing negative feedback signals, are discussed in detail with respect to both their mathematical and biological properties.     

Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth

ABSTRACT: BACKGROUND: The role of the immune system in tumor progression has been subject to 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 vaccines

Vaccination against tumor, either as a prophylactic procedure or as a mode of treatment, has been a distant goal of immunologists for many years. Ideally, the less specific therapies such as chemotherapy would be replaced by an anti-tumor immune response in the host that would be present on a continuing basis. However, progress has been hampered by a lack of understanding of the role of viruses in human tumor development and the molecular nature of tumor-associated antigens. Recent developments using the techniques of molecular biology and monoclonal antibody reagents are beginning to remedy this deficiency so that vaccination has become a real possibility for certain human cancers. The natural fluctuations in growth rates of some human tumors, and the observation that tumors can occasionally remain dormant for years, has led to the idea that the host has an intrinsic ability to control tumor growth, and that this ability is a property of the immune system. Attempts to enhance this putative control are being made by treating the host with defined biological modifiers that stimulate cells involved in immunity in vivo, and by seeking and expanding such cells in vitro before reinfusing them into the host. These attempts to harness the immune system to attack tumor cells that have evaded the host's defenses might be considered optimistic, but they will at least tell us a great deal about tumor cell behavior and the ability of the host to influence it.     

Brain tumor inhibition in experimental model by restorative immunotherapy with a corpuscular antigen

In view of the advances in our understanding of anti-tumor immune response, it is now tempting to contemplate the development of immunotherapies for malignant brain tumors, for which no effective treatment exists. Immunotherapy, with agents known as biological response modifiers (BRMs) are thus gaining increasing interest as the fourth modality of treatment. A non-specific BRM, sheep erythrocytes (SRBC) when administered (ip, 7% PCV/V, 0.5 ml) in a group of animals at the end of seventh month of ethylnitrosourea administration, resulted in significant increase in the mean survival time (> 350 days). Studies conducted for growth kinetics pattern with proliferation index and fluorochrome (HO-33342) uptake techniques at the tissue culture level exhibited a regulatory inhibition of the cells isolated from tissue excised from the tumor susceptible area of brain of SRBC treated animals. Moreover, histological examination of brain from animals showed immunomodulatory role of SRBC in experimentally induced brain tumor. Further probe into the mechanisms involving immunological investigations at the cellular level in these animals indicated an augmented and potentiated cell mediated immune response (CMI) as evidenced by enhanced spontaneous rosette forming capacity and cytotoxic activity of lymphocytes and neutrophil (PMN) mediated phagocytosis respectively. The observations suggest that SRBC down regulate malignant growth pattern of experimental brain tumors either by an immunologically enhanced killing of tumor cells and/or by directly inhibiting the tumor growth possibly via a stimulated cytokine network. Thus, a corpuscular antigen, can potentiate CMI response in experimentally induced brain tumor animal model, in which response induced in the periphery are able to mediate anti-tumor effects in the brain.     

Neutrophil serine proteases fine-tune the inflammatory response

Neutrophil serine proteases are granule-associated enzymes known mainly for their function in the intracellular killing of pathogens. Their extracellular release upon neutrophil activation is traditionally regarded as the primary reason for tissue damage at the sites of inflammation. However, studies over the past several years indicate that neutrophil serine proteases may also be key regulators of the inflammatory response. Neutrophil serine proteases specifically process and release chemokines, cytokines, and growth factors, thus modulating their biological activity. In addition, neutrophil serine proteases activate and shed specific cell surface receptors, which can ultimately prolong or terminate cytokine-induced responses. Moreover, it has been proposed that these proteases can impact cell viability through their caspase-like activity and initiate the adaptive immune response by directly activating lymphocytes. In summary, these studies point to neutrophil serine proteases as versatile mediators that fine-tune the local immune response and identify them as potential targets for therapeutic interventions.     

Interleukin 18: Friend or foe in cancer

In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding.     

Within-host population dynamics and the evolution of microparasites in a heterogeneous host population

Abstract Why do parasites harm their hosts? The general understanding is that if the transmission rate and virulence of a parasite are linked, then the parasite must harm its host to maximize its transmission. The exact nature of such trade‐offs remains largely unclear, but for vertebrate hosts it probably involves interactions between a microparasite and the host immune system. Previous results have suggested that in a homogeneous host population in the absence of super‐ or coinfection, within‐host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population. We incorporate the simplest form of heterogeneity–random heterogeneity in the parameters describing the size of the initial parasite inoculum, the immune response of the host, and the lethal density at which the parasite kills the host. We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite‐induced host mortality) increases with heterogeneity. Finally, we link the within‐host and between‐host dynamics of parasites. We show how the parameters for epidemiological spread of the disease can be estimated from the within‐host dynamics, and in doing so examine the way in which trade‐offs between these epidemiological parameters arise as a consequence of the interaction of the parasite and the immune response of the host.     

Interactions between macrophages and T-lymphocytes: tumor sneaking through intrinsic to helper T cell dynamics

In a mathematical model of the cellular immune response we investigate immune reactions to tumors that are introduced in various doses. The model represents macrophage T-lymphocyte interactions that generate cytotoxic macrophages and cytotoxic T-lymphocytes. In this model antigens (tumors) can induce infinitely large T-lymphocyte effector populations because effector T-lymphocytes are capable of repeated proliferation and we have omitted immunosuppression. In this (proliferative) model small doses of weakly antigenic tumors grow infinitely large (i.e. sneak through) eliciting an immune response of limited magnitude. Intermediate doses of the same tumor induce larger immune responses and are hence rejected. Large doses of the tumor break through, but their progressive growth is accompanied by a strong immune response involving extensive lymphocyte proliferation. Similarly a more antigenic tumor is rejected in intermediate doses and breaks through in large doses. Initially small doses however lead to tumor dormancy. Thus although the model is devoid of explicit regulatory mechanisms that limit the magnitude of its response (immunosuppression is such a mechanism), the immune response to large increasing tumors may either be a stable reaction of limited magnitude (experimentally known as tolerance or unresponsiveness) or a strong and ever increasing reaction. Unresponsiveness can evolve because in this model net T-lymphocyte proliferation requires the presence of a minimum number of helper T cells (i.e. a proliferation threshold). Unresponsiveness is caused by depletion of helper T cell precursors.     

The role of CXC chemokines and their receptors in the progression and treatment of tumors

Chemokines are a class of functional chemotactic peptides that contribute to a number of tumor-related processes. They are functionally defined as soluble factors that are able to control the directional migration of leukocytes, in particular, during infection and inflammation. It appears, however, that the biological effects mediated by chemokines are far more complex, and virtually all cells, including many tumor cell types, can express chemokines and chemokine receptors. A growing body of evidence indicates that they also contribute to a number of tumor-related processes, such as tumor cell growth, angiogenesis/angiostasis, local invasion, and mediate organ-specific metastases of cancer. The CXC chemokine class is a subfamily of a large family of chemokines. During the occurrence and development of tumor cells, this chemokine class is often accompanied by a series of molecular and biological changes. The CXC chemokine subfamily is closely related to the body’s immune response to tumors and biological behaviors of tumors. In this paper, CXC chemokines and their role in the progression and treatment of tumors will be reviewed.