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Review
. 2008 Apr:222:192-205.
doi: 10.1111/j.1600-065X.2008.00606.x.

Signaling defects in anti-tumor T cells

Alan B Frey  1 , Ngozi Monu
Affiliations
Review

Signaling defects in anti-tumor T cells

Alan B Frey et al. Immunol Rev. 2008 Apr.

Abstract

The immune response to cancer has been long recognized, including both innate and adaptive responses, showing that the immune system can recognize protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumor, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumors produce antigens and that priming occurs. Unfortunately, just as obviously, tumors grow, implying that anti-tumor immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumor immunity is suppressed. Both possibilities are supported by current data. In experimental animal models of cancer and also in patients, systemic immunity is usually not dramatically suppressed, because tumor-bearing animals and patients develop T-cell-dependent immune responses to microbes and to either model antigens or experimental cancer vaccines. However, inhibition of specific anti-tumor immunity is common, and several possible explanations of tolerance to tumor antigens or tumor-induced immunesuppression have been proposed. Inhibition of effective anti-tumor immunity results from the tumor or the host response to tumor growth, inhibiting the activation, differentiation, or function of anti-tumor immune cells. As a consequence, anti-tumor T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumor T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumor T cells, and the vanguard of experimental therapy now focuses on vaccination in combination with blockade of immunosuppressive mechanisms. This review discusses several potential mechanisms by which anti-tumor T cells may be inhibited in function.

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Figures

Fig. 1
Fig. 1
Schematic of proximal TCR signaling in lytic TIL
Fig. 2
Fig. 2
Schematic of activation of p56lck
Fig. 3
Fig. 3
Recruitment of Shp-1 to the plasma membrane into proximity with p56lck is mediated by activation (tyrosine phosphorylation) of an inhibitory signaling receptor containing ITIM motifs
Fig. 4
Fig. 4
ITIM motifs are phosphorylated by tyrosine kinases requiring interaction of the inhibitory signaling receptor with its cognate ligand
Fig. 5
Fig. 5
Schematic of tonic balance of p56lck activation
Fig. 6
Fig. 6
Schematic of proximal TCR signaling in non-lytic TIL emphasizing inhibition of p56lck activity by Shp-1
See this image and copyright information in PMC

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