Trends in Immunology
ReviewThe three main stumbling blocks for anticancer T cells
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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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.