Invited article
Mobilizing the low-avidity T cell repertoire to kill tumors

https://doi.org/10.1016/j.semcancer.2007.06.006Get rights and content

Abstract

Optimally, T cells destroy infected and transformed cells of the host. To be effective the T cell repertoire must have a sufficiently diverse number of T cell receptors (TCRs) to recognize the abundance of foreign and tumor antigens presented by MHC molecules. The T cell repertoire must also not be reactive toward self-antigens on healthy cells to prevent autoimmunity. Unlike antigens derived from pathogens, most tumor-associated antigens (TAA) are also self-antigens. Therefore, central and peripheral tolerance mechanisms delete or inhibit tumor-reactive T cells. Although there are T cells within the peripheral repertoire that recognize TAA, these T cells are not sufficient to prevent growth of clinically relevant tumors. We will discuss how this dysfunction results, in part, from the low functional avidity of T cells for tumor, or antigen presenting cells (APC) displaying TAA. We discuss the limitations of these low-avidity tumor-reactive T cells and review current immunotherapies aimed at enhancing the avidity and antitumor activity of the tumor-specific T cell repertoire.

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.

References (165)

  • S. Webb et al.

    Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity

    Cell

    (1990)
  • R.T. Prehn et al.

    Immunity to methylcholanthrene-induced sarcomas

    J Natl Cancer Inst

    (1957)
  • L. Gross

    Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line

    Cancer Res

    (1943)
  • D. Nagorsen et al.

    Natural T cell immunity against cancer

    Clin Cancer Res

    (2003)
  • C.G. Clemente et al.

    Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma

    Cancer

    (1996)
  • M.C. Mihm et al.

    Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response

    Lab Invest

    (1996)
  • W.H. Clark et al.

    Model predicting survival in stage I melanoma based on tumor progression

    J Natl Cancer Inst

    (1989)
  • L. Zhang et al.

    Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer

    N Engl J Med

    (2003)
  • Y. Naito et al.

    CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer

    Cancer Res

    (1998)
  • K. Schumacher et al.

    Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas

    Cancer Res

    (2001)
  • J. Galon et al.

    Type, density, and location of immune cells within human colorectal tumors predict clinical outcome

    Science

    (2006)
  • C. Uyttenhove et al.

    Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase

    Nat Med

    (2003)
  • W. Zou et al.

    T cells, tumour immunity and immunotherapy

    Nat Rev Immunol

    (2006)
  • R. Derynck et al.

    Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells

    Nature

    (1985)
  • S. Kruger-Krasagakes et al.

    Expression of interleukin 10 in human melanoma

    Br J Cancer

    (1994)
  • T.F. Gajewski et al.

    Immune resistance orchestrated by the tumor microenvironment

    Immunol Rev

    (2006)
  • M.A. Alexander-Miller et al.

    Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy

    Proc Natl Acad Sci USA

    (1996)
  • A. Gallimore et al.

    Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides

    J Exp Med

    (1998)
  • V. Rubio et al.

    Ex vivo identification, isolation and analysis of tumor-cytolytic T cells

    Nat Med

    (2003)
  • S. Valitutti et al.

    Serial triggering of many T-cell receptors by a few peptide–MHC complexes

    Nature

    (1995)
  • A.M. Kalergis et al.

    Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex

    Nat Immunol

    (2001)
  • T.W. McKeithan

    Kinetic proofreading in T-cell receptor signal transduction

    Proc Natl Acad Sci USA

    (1995)
  • C. Wulfing et al.

    Kinetics and extent of T cell activation as measured with the calcium signal

    J Exp Med

    (1997)
  • J.D. Rabinowitz et al.

    Kinetic discrimination in T-cell activation

    Proc Natl Acad Sci USA

    (1996)
  • S. Valitutti et al.

    Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy

    J Exp Med

    (1996)
  • M.A. Alexander-Miller et al.

    Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL

    J Exp Med

    (1996)
  • G.J. Kersh et al.

    Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands

    J Exp Med

    (1996)
  • K. Matsui et al.

    Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness

    Proc Natl Acad Sci USA

    (1994)
  • R.H. McMahan et al.

    Relating TCR–peptide–MHC affinity to immunogenicity for the design of tumor vaccines

    J Clin Invest

    (2006)
  • X.Z. Yu et al.

    CD28 signal enhances apoptosis of CD8 T cells after strong TCR ligation

    J Immunol

    (2003)
  • T. Ueno et al.

    Functionally impaired HIV-specific CD8 T cells show high affinity TCR–ligand interactions

    J Immunol

    (2004)
  • M.M. Davis et al.

    Ligand recognition by alpha beta T cell receptors

    Annu Rev Immunol

    (1998)
  • C. Yee et al.

    Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide–MHC tetramers

    J Immunol

    (1999)
  • K.E. de Visser et al.

    Low-avidity self-specific T cells display a pronounced expansion defect that can be overcome by altered peptide ligands

    J Immunol

    (2001)
  • M.A. Derby et al.

    Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining

    Int Immunol

    (2001)
  • V. Dutoit et al.

    Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes

    Eur J Immunol

    (2002)
  • T.N. Bullock et al.

    Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice

    J Immunol

    (2001)
  • V. Dutoit et al.

    Functional avidity of tumor antigen-specific CTL recognition directly correlates with the stability of MHC/peptide multimer binding to TCR

    J Immunol

    (2002)
  • K.C. Garcia et al.

    CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes

    Nature

    (1996)
  • I.F. Luescher et al.

    CD8 modulation of T-cell antigen receptor–ligand interactions on living cytotoxic T lymphocytes

    Nature

    (1995)
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