20.109(S10):Notebook/WF Purple Group Research Project

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Project Overview

  • Our project looks to investigate the unusual extracellular environment in tumors, namely the altered presence of cytokines. Presence of cytokines such as IL-23 allow the tumors to go undetected by the body’s immune response and allows them to grow. We are proposing an aptamer-based approach that would target those cytokines specifically present in malignant tumor cells that would inhibit them and thus make tumors recognizable to the body’s immune mechanism.

Background

  • Inflammation is associated with malignancy, and could possibly have the same mechanism. Both kinds of inflammation (chronic and tumor-associtated) involve stimulating infiltration of immune cells, increasing matrix metalloproteases, and promoting angiogenesis. Production of one cytokine specifically, interleukin 23 (IL-23), is increased in tumors, causing increased production of matrix metalloprotease MMP9, angiogenesis, and reduced T-cell infiltration. Removing IL-23 attracts cytotoxic T cells to the tumor, allowing an immune response to the tumor. IL-23 is an important factor mediating pro-inflammatory processes, which in cancer cells, allows tumors to go unchallenged by an immune response.
  • In creating an aptamer specific for IL-23, we must be wary that IL-23 is very closely related to other cytokines (IL-12) and that our aptamer should bind to only the desired cytokine. This will require testing our selected aptamer in multiple environments, ensuring that it binds to only the cytokines we want and not to others, which could cause undesired side effects.
  • Aptamers have been developed for a few cytokines, e.g. interferon-gamma (IFN). This means that it is most likely possible to isolate aptamers of other cytokines, namely the ones that are prevalent in tumors. Development of aptamers that inhibit the function of cytokines could prevent the tumor from escaping detection by the immune system, allowing the body’s immune response to react appropriately and prevent or inhibit the malignancy.

References

  • Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer 2004;(4):11-22
    • This paper is a review of general extracellular environment in tumors and how cytokines can promote tumor growth by limiting an immune response.
  • Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M. IL-23 promotes tumour incidence and growth. Nature 2006;442(7101):461-5
    • Langowski et al. describes several factors involved in tumor progression. The authors show that the IL-23 cytokine is present at increase levels in human tumors, promotes tumor growth, and limits immune suppression.
  • Min K, Cho M, Han SY, Shim YB, Ku J, Ban C. A simple and direct electrochemical detection of interferon-gamma using its RNA and DNA aptamers. Biosens Bioelectron 2008;23(12):1819-24.
    • This paper provides another example for using aptamers to bind cytokines, namely the interferon-gamma protein. The paper outlines the methods for using binding aptamers for detection of specific cytokines.
  • Van de Vosse E, Lichtenauer-Kaligis EG, van Dissel JT, Ottenhoff TH. Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for IL-12 and IL-23 receptor structure and function. Immunogenetics 2003 Mar;54(12):817-829
    • This paper describes the IL-23 protein and its similarities to IL-12. Namely, it shares a subunit with the IL-12 protein. Our goal is to find an aptamer that will bind specifically to IL-23 so we must negatively select for IL-12 binders.

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