Induction of T-cell memory by a dendritic cell vaccine: a computational model

Bioinformatics, Jul 2014

Motivation: Although results from phase III clinical trials substantially support the use of prophylactic and therapeutic vaccines against cancer, what has yet to be defined is how many and how frequent boosts are needed to sustain a long-lasting and protecting memory T-cell response against tumor antigens. Common experience is that such preclinical tests require the sacrifice of a relatively large number of animals, and are particularly time- and money-consuming. Results: As a first step to overcome these hurdles, we have developed an ordinary differential equation model that includes all relevant entities (such as activated cytotoxic T lymphocytes and memory T cells), and investigated the induction of immunological memory in the context of wild-type mice injected with a dendritic cell-based vaccine. We have simulated the biological behavior both in the presence and in the absence of memory T cells. Comparing results of ex vivo and in silico experiments, we show that the model is able to envisage the expansion and persistence of antigen-specific memory T cells. The model might be applicable to more complex vaccination schedules and substantially in any biological condition of prime-boosting. Availability and implementation: The model is fully described in the article. Contact: fp{at}francescopappalardo.net Supplementary information: Supplementary data are available at Bioinformatics online.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://bioinformatics.oxfordjournals.org/content/30/13/1884.full.pdf

Induction of T-cell memory by a dendritic cell vaccine: a computational model

Induction of T-cell memory by a dendritic cell vaccine: a computational model Francesco Pappalardo 2 y Marzio Pennisi 1 y Alessia Ricupito 0 Francesco Topputo 4 Matteo Bellone 3 Associate Editor: Ziv Bar-Joseph 0 San Raffaele Scientific Institute and Universit a` Vita Salute San Raffaele , 20132 Milan 1 Department of Mathematics and Computer Science, University of Catania , 95125 Catania 2 Department of Drug Science 3 San Raffaele Scientific Institute , 20132 Milan , Italy 4 Politecnico di Milano , 20133 Milano Motivation: Although results from phase III clinical trials substantially support the use of prophylactic and therapeutic vaccines against cancer, what has yet to be defined is how many and how frequent boosts are needed to sustain a long-lasting and protecting memory T-cell response against tumor antigens. Common experience is that such preclinical tests require the sacrifice of a relatively large number of animals, and are particularly time- and money-consuming. Results: As a first step to overcome these hurdles, we have developed an ordinary differential equation model that includes all relevant entities (such as activated cytotoxic T lymphocytes and memory T cells), and investigated the induction of immunological memory in the context of wild-type mice injected with a dendritic cell-based vaccine. We have simulated the biological behavior both in the presence and in the absence of memory T cells. Comparing results of ex vivo and in silico experiments, we show that the model is able to envisage the expansion and persistence of antigen-specific memory T cells. The model might be applicable to more complex vaccination schedules and substantially in any biological condition of prime-boosting. Availability and implementation: The model is fully described in the article. Contact: Supplementary information: Supplementary data are available at Bioinformatics online. 1 INTRODUCTION In the past years both therapeutic and preventive vaccines have been developed with the aim to fight and prevent different types of cancers (Kahn, 2009; Kantoff, 2010; Kenter et al., 2009). The power of vaccines relies on their ability to stimulate a strong and long-lasting antigen-specific immune response, mediated both by B and T lymphocytes. Although induction of a protective titer of neutralizing antibodies is the main objective of most of the vaccines against infectious agents, including vaccines to carcinogenic human papillomavirus and hepatitis B virus, which also protect from cervical and liver cancer, respectively (Lollini et al., 2011), *To whom correspondence should be addressed. yThe authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors. evidence in humans that antibodies induced by a vaccine can contribute to antitumor immunity is scanty (Schoenfeld et al., 2010). Conversely, the major goal of both prophylactic and therapeutic vaccines against non-infectious tumors, which account for 80% of all tumors (Lollini et al., 2011), is to induce a long-lasting antigen-specific CD8 T-cell immunity. In support of this concept, high densities of effector memory CD8þ cytotoxic T cells are associated with a longer overall survival in several human cancers (Fridman et al., 2012). Usually, an effective vaccine requires multiple immunizations in the form of prime boost. Several studies have shown that boosting with a different vector carrying the same antigen is better at enhancing immune responses than boosting with the homologous vector. The mechanism underlying this phenomenon is still obscure. Heterologous prime-boost approaches are now widely used in efforts to develop vaccines (Kaufmann, 2010; Sallusto et al., 2010). It is also generally accepted that a strong primary immune response is required to give rise to a large pool of memory cells (Sprent and Surh, 2011). However, what affects the longevity of memory T cells is not fully understood, and much controversy exists regarding the role of antigens in this process (Kaech et al., 2002; Sprent and Surh, 2011; Zinkernagel, 2002). Sustained high amounts of soluble antigens often lead to tolerance or exhaustion both in T and B cells. As a result of exhaustion, antigen-specific T and B cells express a variety of inhibitory receptors such as PD-1, LAG-3, CD244, CD160, TIM-3 and CTLA-4 (Wherry, 2011). Dendritic cell (DC)-based vaccines have been extensively investigated as potential cancer therapeutic vaccines because of the primary role of DCs as antigen presenting cells (APCs) and their unique ability in T-cell priming (Banchereau and Steinman, 1998). DCs pulsed with the antigen of choice induce a potent antigen-specific immune response and favor the generation of the memory pool. This stems from the asymmetric division of engaged naive T cells into effector and memory cells (Chang et al., 2007). Several phase II clinical trials based on the use of DCs pulsed with tumor-associated antigens are ongoing (Finn, 200 (...truncated)


This is a preview of a remote PDF: https://bioinformatics.oxfordjournals.org/content/30/13/1884.full.pdf

Francesco Pappalardo, Marzio Pennisi, Alessia Ricupito, Francesco Topputo, Matteo Bellone. Induction of T-cell memory by a dendritic cell vaccine: a computational model, Bioinformatics, 2014, pp. 1884-1891, 30/13, DOI: 10.1093/bioinformatics/btu059