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Stochastic modeling of tumor progression and immune evasion.

ABSTRACT: It is now well-established that the host's adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. Tumor acquisition of immune evasive phenotypes, such as class-I MHC down-regulation, remains a major limitation of successful T-cell immunotherapy. Here, we consider a population dynamical model coupling tumor and adaptive immune compartments in order to study the dynamics and survival of an evolving threat when faced with adaptive immune pressure. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. We parameterize adaptive immune functioning by T-cell turnover and repertoire diversity and predict that decreases in the latter quantity which occur in advanced age may substantially affect the ability to recognize, and therefore control, an immune evasive threat like cancer. This framework recapitulates general features of age-dependent AML incidence, thereby providing a probable association between cancer frequency and adaptive immune functioning. Lastly, we quantify therapeutic efficacy of adjuvant immunotherapeutic strategies, and predict their benefits and limitations with regard to handling immune evasion. Our model generates survival behavior consistent with known growth-dependent characteristics, and serves as a first attempt at modeling stochastic cancer evolution alongside an adaptive immune compartment.

SUBMITTER: George JT

PROVIDER: S-EPMC6225903 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Stochastic modeling of tumor progression and immune evasion.

George Jason T JT Levine Herbert H

Journal of theoretical biology 20180912

It is now well-established that the host's adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. Tumor acquisition of immune evasive phenotypes, such as class-I MHC down-regulation, remains a major limitation of successful T-cell ...[more]

PMID: 30218648

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Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.

Dataset Information

Stochastic modeling of tumor progression and immune evasion.

Publications

Stochastic modeling of tumor progression and immune evasion.

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