Dataset Information

A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy.

ABSTRACT: TGF-? is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-? inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-? and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-? concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-? treatment, vaccine treatment, and combined anti-TGF-? vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.

SUBMITTER: Wilson S

PROVIDER: S-EPMC3822329 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy.

Wilson Shelby S Levy Doron D

Bulletin of mathematical biology 20120322 7

TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor ...[more]

PMID: 22438084

Similar Datasets

Project description:Triple-negative breast cancer (TNBC), as one of the most aggressive forms of breast cancer, is characterized by a poor prognosis and a very low rate of disease-free and overall survival. In recent years, immunotherapeutic approaches targeting T cell checkpoint molecules, such as cytotoxic lymphocyte antigen-4 (CTLA-4), programmed death1 (PD-1) or its ligand, programmed death ligand 1 (PD-L1), have shown great potential and have been used to treat various cancers as single therapies or in combination with other modalities. However, despite this remarkable progress, patients with TNBC have shown a low response rate to this approach, commonly developing resistance to immune checkpoint blockade, leading to treatment failure. Extracellular acidosis within the tumor microenvironment (also known as the Warburg effect) is one of the factors preventing immune cells from mounting effective responses and contributing to immunotherapy treatment failure. Therefore, reducing tumor acidity is important for increasing cancer immunotherapy effectiveness and this has yet to be realized in the TNBC environment. In this study, the oral administration of sodium bicarbonate (NaHCO3) enhanced the antitumor effect of anti-PD-L1 antibody treatment, as demonstrated by generated antitumor immunity, tumor growth inhibition and enhanced survival in 4T1-Luc breast cancer model. Here, we show that NaHCO3 increased extracellular pH (pHe) in tumor tissues in vivo, an effect that was accompanied by an increase in T cell infiltration, T cell activation and IFN-γ, IL2 and IL12p40 mRNA expression in tumor tissues, as well as an increase in T cell activation in tumor-draining lymph nodes. Interestingly, these changes were further enhanced in response to combined NaHCO3 + anti-PD-L1 therapy. In addition, the acidic extracellular conditions caused a significant increase in PD-L1 expression in vitro. Taken together, these results indicate that alkalizing therapy holds potential as a new tumor microenvironment immunomodulator and we hypothesize that NaHCO3 can enhance the antitumor effects of anti-PD-L1 breast cancer therapy. The combination of these treatments may have an exceptional impact on future TNBC immunotherapeutic approaches by providing a powerful personalized medicine paradigm. Therefore, our findings have a great translational potential for improving outcomes in TNBC patients.

Dataset Information

A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy.

Publications

A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets