Effects of delayed immune-response in tumor immune-system interplay

Tumors constitute a wide family of diseases kinetically characterized by the co-presence of multiple spatio-temporal scales. So, tumor cells ecologically interplay with other kind of cells, e.g. endothelial cells or immune system effectors, producing and exchanging various chemical signals. As such, tumor growth is an ideal object of hybrid modeling where discrete stochastic processes model agents at low concentrations, and mean-field equations model chemical signals. In previous works we proposed a hybrid version of the well-known Panetta-Kirschner mean-field model of tumor cells, effector cells and Interleukin-2. Our hybrid model suggested -at variance of the inferences from its original formulation- that immune surveillance, i.e. tumor elimination by the immune system, may occur through a sort of side-effect of large stochastic oscillations. However, that model did not account that, due to both chemical transportation and cellular differentiation/division, the tumor-induced recruitment of immune effectors is not instantaneous but, instead, it exhibits a lag period. To capture this, we here integrate a mean-field equation for Interleukins-2 with a bi-dimensional delayed stochastic process describing such delayed interplay. An algorithm to realize trajectories of the underlying stochastic process is obtained by coupling the Piecewise Deterministic Markov process (for the hybrid part) with a Generalized Semi-Markovian clock structure (to account for delays). We (i) relate tumor mass growth with delays via simulations and via parametric sensitivity analysis techniques, (ii) we quantitatively determine probabilistic eradication times, and (iii) we prove, in the oscillatory regime, the existence of a heuristic stochastic bifurcation resulting in delay-induced tumor eradication, which is neither predicted by the mean-field nor by the hybrid non-delayed models

Stochastic Hybrid Automata with delayed transitions to model biochemical systems with delays

To study the effects of a delayed immune-response on the growth of an immuno- genic neoplasm we introduce Stochastic Hybrid Automata with delayed transi- tions as a representation of hybrid biochemical systems with delays. These tran- sitions abstractly model unknown dynamics for which a constant duration can be estimated, i.e. a delay. These automata are inspired by standard Stochastic Hybrid Automata, and their semantics is given in terms of Piecewise Determin- istic Markov Processes. The approach is general and can be applied to systems where (i) components at low concentrations are modeled discretely (so to retain their intrinsic stochastic fluctuations), (ii) abundant component, e.g., chemical signals, are well approximated by mean-field equations (so to simulate them efficiently) and (iii) missing components are abstracted with delays. Via sim- ulations we show in our application that interesting delay-induced phenomena arise, whose quantification is possible in this new quantitative framewor

Fighting viral infections and virus-driven tumors with cytotoxic CD4+ T cells

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors

Immune targets in the tumor microenvironment treated by radiotherapy.

Radiotherapy (RT), the major anti-cancer modality for more than half of cancer patients after diagnosis, has the advantage of local tumor control with relatively less systematic side effects comparing to chemotherapy. However, the efficacy of RT is limited by acquired tumor resistance leading to the risks of relapse and metastasis. To further enhance the efficacy of RT, with the renaissances of targeted immunotherapy (TIT), increasing interests are raised on RT combined with TIT including cancer vaccines, T-cell therapy, and antibody-based immune checkpoint blockers (ICB) such as anti-CTLA-4 and anti-PD1/PD-L1. In achieving a significant synergy between RT and TIT, the dynamics of radiation-induced response in tumor cells and stromal cells, especially the cross-talk between tumor cells and immune cells in the irradiated tumor microenvironment (ITME) as highlighted in recent literature are to be elucidated. The abscopal effect refereeing the RT-induced priming function outside of ITME could be compromised by the immune-suppressive factors such as CD47 and PD-L1 on tumor cells and Treg induced or enhanced in the ITME. Cell surface receptors temporally or permanently induced and bioactive elements released from dead cells could serve antigenic source (radiation-associated antigenic proteins, RAAPs) to the host and have functions in immune regulation on the tumor. This review is attempted to summarize a cluster of factors that are inducible by radiation and targetable by antibodies, or have potential to be immune regulators to synergize tumor control with RT. Further characterization of immune regulators in ITME will deepen our understanding of the interplay among immune regulators in ITME and discover new effective targets for the combined modality with RT and TIT

Circulating markers of ageing and allostatic load: a slow train coming

Dealing with the growing burden of age-related morbidities is one of the greatest challenges facing modern society. How we age across the lifecourse and how psychosocial and lifestyle factors interplay with the biology of ageing remains to be fully elucidated. Sensitive and specific biomarkers with which to interrogate the biology of the ageing process are sparse. Recent evidence suggests that non-coding RNAs are key determinants of such processes and that these can be used as potential circulatory bio-markers of ageing. They may also provide a mechanism which mediates the spread of allostatic load across the body over time, ultimately reflecting the immunological health and physiological status of tissues and organs. The interplay between exosomal microRNAs and ageing processes is still relatively unexplored, although circulating microRNAs have been linked to the regulation of a range of physiological and pathological processes and offer insight into mechanistic determinants of healthspan

The role of mucosal immunity in the pathogenesis of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of prematurity. Although the precise cause is not well understood, the main risk factors thought to contribute to NEC include prematurity, formula feeding, and bacterial colonization. Recent evidence suggests that NEC develops as a consequence of intestinal hyper-responsiveness to microbial ligands upon bacterial colonization in the preterm infant, initiating a cascade of aberrant signaling events, and a robust pro-inflammatory mucosal immune response. We now have a greater understanding of important mechanisms of disease pathogenesis, such as the role of cytokines, immunoglobulins, and immune cells in NEC. In this review, we will provide an overview of the mucosal immunity of the intestine and the relationship between components of the mucosal immune system involved in the pathogenesis of NEC, while highlighting recent advances in the field that have promise as potential therapeutic targets. First, we will describe the cellular components of the intestinal epithelium and mucosal immune system and their relationship to NEC. We will then discuss the relationship between the gut microbiota and cell signaling that underpins disease pathogenesis. We will conclude our discussion by highlighting notable therapeutic advancements in NEC that target the intestinal mucosal immunity

Oncogenic senescence: a multi-functional perspective.

Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer. Although oncogenic mutations are capable of inducing a beneficial senescence response that prevents the growth of premalignant cells and promotes cancer immune-surveillance, the secretome of senescent cells also includes factors with pro-tumorigenic properties. On June 23rd and 24th, 2016, the Division of Cancer Biology of the National Cancer Institute sponsored a workshop to discuss the complex role of cellular senescence in tumorigenesis with the goal to define the major challenges and opportunities within this important field of cancer research. Additionally, it was noted how the development of novel tools and technologies are required to accelerate research into a mechanistic understanding of senescent cells in carcinogenesis in order to overcome the current limitations in this exciting, yet ill-defined area

The effects of distributed life cycles on the dynamics of viral infections

We explore the role of cellular life cycles for viruses and host cells in an infection process. For this purpose, we derive a generalized version of the basic model of virus dynamics (Nowak, M.A., Bangham, C.R.M., 1996. Population dynamics of immune responses to persistent viruses. Science 272, 74-79) from a mesoscopic description. In its final form the model can be written as a set of Volterra integrodifferential equations. We consider the role of age-distributed delays for death times and the intracellular (eclipse) phase. These processes are implemented by means of probability distribution functions. The basic reproductive ratio $R_0$ of the infection is properly defined in terms of such distributions by using an analysis of the equilibrium states and their stability. It is concluded that the introduction of distributed delays can strongly modify both the value of $R_0$ and the predictions for the virus loads, so the effects on the infection dynamics are of major importance. We also show how the model presented here can be applied to some simple situations where direct comparison with experiments is possible. Specifically, phage-bacteria interactions are analysed. The dynamics of the eclipse phase for phages is characterized analytically, which allows us to compare the performance of three different fittings proposed before for the one-step growth curve

Dissecting interferon-induced transcriptional programs in human peripheral blood cells

Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings