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  • Review Article
  • Published:

Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses

Nature Reviews Cancer volume 2, pages 409–419 (2002)Cite this article

Key Points

  • The identification of many human tumour antigens as potential targets for immunotherapy has led to clinical trials to augment the tumour immune response through the use of vaccines and adoptively transferred T cells. Immunological monitoring in these studies will be crucial for understanding the principles that underlie successful immunotherapeutic strategies.

  • Recent advances in immunological monitoring now enable more-direct detection of individual antigen-specific T cells on the basis of structural or functional properties. These advanced assays provide a degree of specificity and sensitivity that was not previously possible with classical cytolytic or proliferation assays.

  • Structure-based assays — through the use of peptide–MHC (major histocompatibility complex) multimers that bind antigen-specific T-cell receptors (TCRs), or quantitative polymerase chain reaction (PCR) assays that detect clone-specific regions of the TCR — provide an estimation of the total number of T cells independent of functional status. Such tests are highly sensitive but can be difficult to implement in large-scale studies.

  • Function-based assays — such as ELISPOT analysis, which detects antigen-specific T cells on the basis of proximal cytokine production — provide a reliable measure of the reactive T-cell population and are amenable to high-throughput analysis. However, ELISPOT analysis and other function-based assays — intracellular cytokine analysis, quantitative real-time PCR analysis of cytokine expression — might underestimate or fail to detect naive, anergic or functionally unresponsive antigen-specific T cells.

  • Judicious use of these advanced assays to monitor the immune response in clinical trials can be used to address questions related to the magnitude, homing property, function and avidity of anti-tumour T cells that are required for effective therapy.

  • An important corollary to an evaluation of the T-cell response will be an understanding of the tumour response to immune manipulation, particularly an evaluation of potential mechanisms of immune escape.

  • Pre-clinical and clinical studies have shown that tumour cells might circumvent the immune response through defective antigen expression and presentation, inhibition of T-cell effector function and induction of anti-apoptotic mechanisms.

  • Occasional application of immunological assays to current clinical trials has not always shown a correlation between increased immune response and clinical response. It is anticipated that incorporation of these advanced assays into future trials of antigen-specific immunotherapy, accompanied by evaluation for mechanisms of tumour immune escape, will help to explain these discrepancies and elucidate requirements for more-effective therapy.

Abstract

Advances in immunological monitoring provide the means to analyse the cellular immune response with greater sensitivity and precision than ever before. Novel immunological tools can be used not only to quantify the antigen-specific response, but also to analyse the phenotype and function of individual effector cells. Application of these tools to dissect the antitumour responses will lead to a greater understanding of the principles that underlie successful immunotherapeutic strategies and potential mechanisms of tumour immune evasion.

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Figure 1: Structure-based T-cell assays.
Figure 2: Function-based T-cell assays.
Figure 3: Mechanisms of immune evasion.

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Acknowledgements

This work is supported, in part, by the Cancer Research Institute, National Institutes of Health/National Cancer Institute and the Damon Runyon Cancer Research Foundation. We apologize to authors whose work was not included due to space constraints.

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Authors and Affiliations

  1. Clinical Research Division, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Cassian Yee & Philip Greenberg

  2. Department of Medicine, University of Washington, Seattle, 98195, Washington, USA

    Cassian Yee & Philip Greenberg

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  1. Cassian Yee
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  2. Philip Greenberg
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Correspondence to Cassian Yee.

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DATABASES

Cancer.gov

chronic myelogenous leukaemia

colorectal cancer

melanoma

ovarian cancer

uterine cancer

LocusLink

β2-microglobulin

CD4

CD8

CD45

CD69

CDR3

FAS

FASL

FLICE

FLIP

GM-CSF

granzyme B

IFN-α

IFN-γ

IL-10

IL-12

interleukin-2

MAGE3

MART1

NGFR

NY-ESO-1

PI9

RCAS1

survivin

TNF-α

transforming growth factor-β

Glossary

T-CELL-DEFINED TUMOUR ANTIGENS

Antigens expressed by tumour cells that are recognized by T cells. The types of tumour antigen, and their expression among various tumours and normal tissues are listed in Table 1.

T-CELL RECEPTOR

(TCR). The antigen receptor on CD4+ and CD8+ T cells that recognizes peptides bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells. The most common form of TCR is composed of a heterodimer of α- and β-chains. The α- and β-chains of the TCR are composed of an immunoglobulin (Ig)-like variable domain and an Ig-like constant domain.

LYMPHOKINE-ACTIVATED KILLER CELLS

(LAKs). These immune cells are generated by incubating peripheral-blood lymphocytes with high doses of IL-2 in vitro. LAK cells are comprised of heterogeneous populations of T cells, natural killer cells and other LAK cells, and mediate non-MHC (major histocompatibility complex)-restricted killing.

TUMOUR-INFILTRATING LYMPHOCYTES

(TILs). These immune cells are cultivated from tumour aspirates with the presumption that lymphocytes that infiltrate the tumour are more likely to be tumour specific. TILs are expanded with high doses of IL-2 in vitro and are comprised of heterogeneous populations of T cells and natural killer cells. Adoptive therapy with TILs or LAKs requires co-administration of high-dose IL-2, which can be accompanied by significant morbidity.

IL-2

Interleukin-2. A growth factor for T cells and natural killer (NK) cells. Antigen-specific T cells express high affinity IL-2 receptors after antigen stimulation. NK cells and LAKs express intermediate-affinity IL-2 receptors and require higher doses of IL-2 to promote growth.

CELLULAR IMMUNITY

Immune response mediated by T lymphocytes.

CD4+ AND CD8+ T CELLS

T cells that express the CD4 surface antigen (CD4+ T cells) recognize cognate antigen in the context of the major histocompatibility complex (MHC) class II complex on antigen-presenting cells, and provide helper function to CD8+ T cells through the release of cytokines and the activation of professional antigen-presenting cells. CD8+ T cells recognize cognate antigen in the context of the MHC class I complex, and mediate direct cell killing through the release of lytic proteins.

DTH

Delayed-type hypersensitivity reaction. A skin test that assays for cell-mediated immune reactions. The test reagent (antigen) is injected just under the skin surface, and the resulting immune reaction caused by T-cell-dependent macrophage activation and inflammation causes a visible induration over the injection site that is measured in 'mm of induration'. The reaction is usually representative of a CD4+ T-cell response to antigen.

HUMORAL IMMUNITY

Immune response mediated by antibodies that are produced by B lymphoctyes.

PEPTIDE–MHC COMPLEX

Antigens are processed and presented on the surface of the cell as peptide fragments that are bound within the cleft of molecules encoded by the major histocompatibility complex (MHC) genes. Peptides bound to class I MHCs are recognized by CD8+ T cells. Peptides bound to class II MHCs are recognized by CD4+ T cells. The peptide sequence that is recognized by T cells in the context of the MHC is also known as an epitope.

RESTRICTING ALLELE

The major histocompatibility complex (MHC) allele that presents a given epitope is known as the restricting allele for that epitope. T cells will recognize the epitope only when presented by its restricting allele.

PHENOTYPIC ANTIBODIES

Antibodies to surface or intracellular proteins that provide additional information regarding the developmental, activational or functional state. For example, activated T cells upregulate expression of the early activation marker CD69 on their cell surface.

CDR3

(Complementarity-determining region 3). A highly variable region of the T-cell receptor (in the variable domain) that mediates T-cell recognition of the peptide–MHC complex. T-cell clones express unique CDR3 regions.

PERIPHERAL-BLOOD MONONUCLEAR CELLS

Nucleated cells of the peripheral blood, which include T and B lymphocytes, monocytes and natural killer cells.

RIBOPROBES

Short ribonucleotide fragments tagged with a radioactive conjugate that are used to identify specific mRNA.

T-CELL INFILTRATE

T cells that accumulate at the site of the tumour. An enriched population of tumour-specific T cells have been identified in T-cell infiltrates.

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Yee, C., Greenberg, P. Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses. Nat Rev Cancer 2, 409–419 (2002). https://doi.org/10.1038/nrc820

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