Invited articleMobilizing the low-avidity T cell repertoire to kill tumors
Introduction
Immune recognition of tumors in an antigen-specific manner was first illustrated by experiments involving transplantation of chemically induced tumors into laboratory mice [1], [2]. Specifically, the growth of a transplanted tumor could be prevented by prior exposure to the same tumor, but not a different tumor. Many investigators have since observed naturally developing tumor-specific T cell responses (reviewed in [3]) which, in patients treated with standard therapies, correlate with improved prognosis [4], [5], [6], [7], [8], [9], [10]. Despite this positive correlation, the tumor infiltrating lymphocytes (TIL) do not always control tumor growth. Tumor-specific T cells are ineffective in part due to active regulation and suppression by tumors. For example, tumors produce the tryptophan degrading enzyme indoleamine 2,3-dioxygenase that inhibits T cell proliferation [11]. In addition, tumors produce immune suppressive cytokines such as TGFβ [12], [13] and IL-10 [14]. The mechanism of immune suppression by these cytokines includes the inhibition of proliferation and inflammatory cytokine production by immune cells. For detailed reviews of tumor-induced immune suppression see the other reviews in this issue and [15].
In this review, we focus on another mechanism responsible for the poor reactivity of the tumor-specific T cell repertoire, the low functional avidity of the responding T cells. Functional avidity, or the sensitivity of T cell to antigen, is an important factor influencing the efficacy of a T cell response. Virus-specific cytotoxic T lymphocytes (CTL) with high functional avidity clear viral infections better than T cells with low functional avidity because these CTL are more sensitive to small viral loads [16], [17]. Analysis of the functional avidity of tumor-specific T cells has provided insight into why tumors develop despite the presence of TIL and how these T cells may be harnessed for cancer therapies. In this review we will discuss the factors influencing the functional avidity of CTL and how this affects the T cell response to tumors. Furthermore, we will discuss different approaches aimed at improving the functional avidity of the tumor-specific T cells with the goal of augmenting conventional treatments and T cell therapies against cancer.
Section snippets
Affinity, functional avidity, and recognition efficiency of T cells
As mentioned above, T cell functional avidity is defined as the sensitivity of a T cell to activation by an antigenic peptide bound by an MHC molecule. The sensitivity of a T cell to antigen is influenced by multiple factors: the affinity of the TCR–peptide–MHC interaction, the engagement of multiple other receptors on T cells, and the density of these receptors on the T cell surface. The combination of these binding interactions with an APC determines the functional avidity of a T cell. Since
Tolerance and the tumor-specific T cell repertoire
The immune system maintains a diverse repertoire of T cells with high avidity for foreign antigen while limiting the activity of T cells that recognize self-antigen. Since most tumor antigens are self-antigens, tolerance mechanisms greatly influence the quality of the antitumor T cell response. The degree to which tolerance affects tumor-specific T cells differs depending on the TAA, but in many cases both central and peripheral tolerance mechanisms directly influence the functional avidity of
Enhancing the T cell response to tumors
Can the low-avidity tumor-specific T cell repertoire be manipulated to enhance the immune response to tumors? Typically, the low avidity of TAA-specific T cells for antigen prevents activation of these T cells in response to endogenous levels of tumor antigens. Therapies that enhance antigenic priming of tumor-specific T cells will likely elicit a more productive antitumor response. A number of strategies are being developed to improve the function of these T cells so that they may be used
Discussion
Analyses of the T cell response to tumor antigens have demonstrated that tumor growth still occurs despite large numbers of tumor-reactive T cells. T cells must overcome a number of obstacles including tumor-induced immune suppression, cellular heterogeneity, and antigen loss from the tumor. This poor reactivity of T cells for TAA also results from central and peripheral tolerance mechanisms that delete or inactivate T cells with high avidity for tumor antigens. The remaining low-avidity T
Acknowledgements
We thank Dr. John Cohen, Kimberly Jordan, and Charles Kemmler for critical reading of this manuscript. The authors apologize to those investigators whose research was not cited due to space limitations. The authors were supported by R01 CA109560 and the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology Fellowship.
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