A biased competition theory of cytotoxic T lymphocyte interaction with tumor nodules.

Claire Christophe,Magda Rodrigues,Sabina Müller,Salvatore Valitutti,Loïc Dupré,Patrick Cattiaux,Sébastien Gadat,Anne-Elisabeth Petit

doi:10.1371/journal.pone.0120053

Abstract

The dynamics of the interaction between Cytotoxic T Lymphocytes (CTL) and tumor cells has been addressed in depth, in particular using numerical simulations. However, stochastic mathematical models that take into account the competitive interaction between CTL and tumors undergoing immunoediting, a process of tumor cell escape from immunesurveillance, are presently missing. Here, we introduce a stochastic dynamical particle interaction model based on experimentally measured parameters that allows to describe CTL function during immunoediting. The model describes the competitive interaction between CTL and melanoma cell nodules and allows temporal and two-dimensional spatial progression. The model is designed to provide probabilistic estimates of tumor eradication through numerical simulations in which tunable parameters influencing CTL efficacy against a tumor nodule undergoing immunoediting are tested. Our model shows that the rate of CTL/tumor nodule productive collisions during the initial time of interaction determines the success of CTL in tumor eradication. It allows efficient cytotoxic function before the tumor cells acquire a substantial resistance to CTL attack, due to mutations stochastically occurring during cell division. Interestingly, a bias in CTL motility inducing a progressive attraction towards a few scout CTL, which have detected the nodule enhances early productive collisions and tumor eradication. Taken together, our results are compatible with a biased competition theory of CTL function in which CTL efficacy against a tumor nodule undergoing immunoediting is strongly dependent on guidance of CTL trajectories by scout siblings. They highlight unprecedented aspects of immune cell behavior that might inspire new CTL-based therapeutic strategies against tumors.

Highlights

Cytotoxic T Lymphocytes (CTL) destroy virally infected cells and tumor cells via the secretion of lytic molecules stored in intracellular granules [1]
Having established the basic parameters of the model, we employed numerical simulations to compute the probability of success of CTL in eradicating the tumor nodule without chemotactism, i.e. meaning that CTL motility is driven by a pure symmetric random walk
For CTL success, it was important that a minimum number of CTL/tumor cell productive collisions would occur during the early time points of CTL/tumor cell dynamic confrontation

Summary

Introduction

CTL destroy virally infected cells and tumor cells via the secretion of lytic molecules stored in intracellular granules [1]. While CTL can control tumor growth by destroying tumor cells, the selective pressure of the immune system promotes tumor progression by selecting tumor variants that are fit to survive in an immunocompetent host. Such a process is defined as cancer immunoediting [6]. One possibility would be to facilitate the access of CTL to the tumor site in order to eradicate the tumor before immunoediting can occur In this context, an attractive hypothesis is that CTL might serve as scouts of their siblings. Whether chemotactic responses of CTL to chemokine released by other CTL having contacted the tumor nodule could be exploited in the context of antitumor therapeutic strategies remains to be elucidated

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