The three main stumbling blocks for anticancer T cells

doi:10.1016/j.it.2012.02.006

Trends in Immunology

Volume 33, Issue 7, July 2012, Pages 364-372

https://doi.org/10.1016/j.it.2012.02.006 Get rights and content

Memory and effector T cells have the potential to counteract cancer progression, but often fail to control the disease, essentially because of three main stumbling blocks. First, clonal deletion leads to relatively low numbers or low-to-intermediate T cell receptor (TCR) affinity of self/tumor-specific T cells. Second, the poor innate immune stimulation by solid tumors is responsible for inefficient priming and boosting. Third, T cells are suppressed in the tumor microenvironment by inhibitory signals from other immune cells, stroma and tumor cells, which induces T cell exhaustion, as demonstrated in metastases of melanoma patients. State-of-the-art adoptive cell transfer and active immunotherapy can partially overcome the three stumbling blocks. The reversibility of T cell exhaustion and novel molecular insights provide the basis for further improvements of clinical immunotherapy.

Section snippets

Immune responses may support or inhibit cancer progression

The development of immunotherapy for cancer patients takes many years. After the invention of generating monoclonal antibodies (mAbs), about two decades of intense research and development were necessary to establish mAbs as standard therapies [1]. T cell based therapies were initiated later, and require further optimization for reaching widespread clinical application. Nevertheless, there have been major breakthroughs in the past few years, with the introduction of a vaccine for prostate

Progressive loss of functional T cells in cancer

Tumor-specific T cells are subjected to mechanisms of self-tolerance, because many tumor antigens are self-antigens or closely related to self. During thymic maturation, each precursor T cell recombines its unique TCR, which determines its antigen specificity and the affinity to peptide/MHC. Subsequently, T cells are positively selected to assure MHC restriction and negatively selected (clonally deleted) to eliminate self-specific T cells. Although the latter is important to avoid autoimmunity,

T cell intrinsic mechanisms of hyporesponsiveness in chronic infection and autoimmunity

The third stumbling block for self/tumor-specific T cells is the induction and maintenance of T cell hyporesponsiveness, which has been observed in the tumor microenvironment in mice and humans 4, 5, 19, 20. Before discussing the underlying mechanisms in cancer, we examine the two principle states of T cell hyporesponsiveness: anergy and exhaustion (Box 2). T cell anergy has primarily been described in in vitro studies and in models of autoimmunity [21], and T cell exhaustion has been defined

Cellular and molecular characteristics of T cell hyporesponsiveness in cancer

Although much less well studied, some of the mechanisms described above also play a role in cancer and thus hamper effective antitumor immune responses. It has long been recognized that tumors can actively escape the control of anticancer T cells (Box 1) by directly interfering with immune defense mechanisms [34] even when T cells are activated [35].

Dysfunction of effector and memory CD8 and T helper 1 cells is probably frequent in cancer patients. Induction of T cell hyporesponsiveness has

Coexistence of functional and nonfunctional T cells

It has been shown that anticancer T cells from peripheral blood have impaired effector functions in untreated patients [47], and even after immunotherapy 48, 49. However, in the majority of cases, this is due to the stumbling blocks 1 and 2, for example, low T cell numbers or low TCR affinity, and/or incomplete priming, rather than due to suppressive mechanisms. Before one can study possible inhibition of effector and memory T cells, it is important to determine whether immunotherapy has the

Reversibility of hyporesponsiveness

Although some molecular changes associated with hyporesponsiveness can be long lasting due to epigenetic modifications [51], the diminished T cell functionality is often reversible. Isolating the T cells from their immunosuppressive tumor environment can be sufficient to restore their effector functions 9, 19, 52. However, this requires pro-survival and homeostatic cytokines such as IL-7. IL-7 has multiple beneficial effects on effector T cells. It downregulates SOCS3, resulting in enhanced

Implications for T cell-based immunotherapy for cancer patients

Different approaches are required to overcome the three stumbling blocks (Figure 1). The first one calls for substitution with suitable cancer-specific T cells. Genes encoding TCRs [64] or chimeric antigen receptors [65] have been inserted into autologous lymphocytes used for adoptive T cell transfer therapy, demonstrating proof of principle but requiring further development. Enhanced potency of adoptively transferred T cells comes with increased risk of toxicity, mainly because healthy cells

Concluding remarks

The presence of anticancer T cells in the tumor microenvironment correlates with favorable clinical outcome. However, there are several hurdles for effector and memory T cells limiting their potential of protecting from disease. The main stumbling blocks for antitumor T cells are: (i) their low number or low TCR affinity; (ii) their insufficient activation by APCs; and (iii) their functional hyporesponsiveness within the tumor microenvironment. Unraveling the mechanisms responsible for each of

Acknowledgments

We are obliged to all members of our team, and to the very many colleagues around the world for scientific contributions. We apologize for what was not possible to cite in this review. We thank the Swiss National Foundation (3200B0-118123, 310030-135553), the OPO-Stiftung (Switzerland, 2010/11-0039), the Cancer Research Institute, the Cancer Vaccine Collaborative and the Cancer Immunotherapy Consortium (USA) for support.

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Citation Excerpt :
T cells within TME would be modulated to adapt new condition. Firstly, the process of antigen presentation is impaired in TME, leading to insufficient priming and activating of T cell [77]. Cytokines, like IFN-γ and tumor necrosis factor-α (TNF-α), are less expressed in CD4+ T cells and CD8+ T cells as well [78,79].
Over the past few years, tumor immunotherapy has emerged as an innovative tumor treatment and owned incomparable advantages over other tumor therapy. With unique complexity and uncertainty, immunotherapy still need helper to apply in the clinic. Galectins, modulated in tumor microenvironment, can regulate the disorders of innate and adaptive immune system resisting tumor growth. Considering the role of galectins in tumor immunosuppression, combination therapy of targeted anti-galectins and immunotherapy may be a promising tumor treatment. This brief review summarizes the expression and immune functions of different galectins in tumor microenvironment and discusses the potential value of anti-galectins in combination with checkpoint inhibitors in tumor immunotherapy.

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^*: Current address: Department of Cancer Biology, DANA-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

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Trends in Immunology

ReviewThe three main stumbling blocks for anticancer T cells

Section snippets

Immune responses may support or inhibit cancer progression

Progressive loss of functional T cells in cancer

T cell intrinsic mechanisms of hyporesponsiveness in chronic infection and autoimmunity

Cellular and molecular characteristics of T cell hyporesponsiveness in cancer

Coexistence of functional and nonfunctional T cells

Reversibility of hyporesponsiveness

Implications for T cell-based immunotherapy for cancer patients

Concluding remarks

Acknowledgments

Blood

Immunity

Immunity

Immunity

Blood

Curr. Opin. Immunol.

Semin. Immunol.

Immunity

Curr. Opin. Immunol.

Immunity

Pathology (Phila.)

Curr. Opin. Immunol.

Immunity

Immunity

Immunity

Trends Immunol.

Trends Immunol.

Blood

J. Invest. Dermatol.

Curr. Opin. Immunol.

Semin. Cancer Biol.

Curr. Opin. Genet. Dev.

Immunity

Immunity

Trial watch: monoclonal antibodies in cancer therapy

Oncoimmunology

Sipuleucel-T immunotherapy for castration-resistant prostate cancer

N. Engl. J. Med.

Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab

Proc. Natl. Acad. Sci. U.S.A.

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients

J. Exp. Med.

Exhaustion of tumor-specific CD8 T cells in metastases from melanoma patients

J. Clin. Invest.

T cell exhaustion

Nat. Immunol.

The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses

Nat. Rev. Immunol.

PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells

EMBO Mol. Med.

Early T cell signalling is reversibly altered in PD-1 T lymphocytes infiltrating human tumors

PLoS ONE

Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells

Nat. Immunol.

A human memory T cell subset with stem cell-like properties

Nat. Med.

Human TCR-binding affinity is governed by MHC class restriction

J. Immunol.

Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function

J. Immunol.

Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells

Int. J. Cancer

Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance

Cancer Res.

New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting

J. Immunol.

Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery

Proc. Natl. Acad. Sci. U.S.A.

Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection

J. Exp. Med.

High antigen levels are the cause of T cell exhaustion during chronic viral infection

Proc. Natl. Acad. Sci. U.S.A.

PD-1 signaling in primary T cells

Immunol. Rev.

Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells

J. Immunol.

Transcriptional analysis of HIV-specific CD8(+) T cells shows that PD-1 inhibits T cell function by upregulating BATF

Nat. Med.

Review
The three main stumbling blocks for anticancer T cells