Signalling defects in anti-tumour T cells.

Friday, 04/06/2010  |   Bone Cancer  |  no comments

The immune response to cancer has been long recognised, including both innate and adaptive responses, showing that the immune system can recognise protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumour, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumours produce antigens and that priming occurs. Unfortunately, just as obviously, tumours grow, implying that anti-tumour immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumour 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 tumour-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-tumour immunity is common, and several possible explanations of tolerance to tumour antigens or tumour-induced immunesuppression have been proposed. Inhibition of effective anti-tumour immunity results from the tumour or the host response to tumour growth, inhibiting the activation, differentiation, or function of anti-tumour immune cells. As a consequence, anti-tumour T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumour T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumour 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-tumour T cells may be inhibited in function.
Frey, A.B & Monu, N. Signalling defects in anti-tumour T cells. 2008 Immunological reviews. Vol 222; Pp.192-205 ISSN: 1600-065X

Signal transducer and activator of transcription 3 (STAT3) has emerged as a critical regulator for tumour-associated inflammation. Activation of STAT3 negatively regulates the Th1-type immune response and promotes expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T-cell functions in the tumour microenvironment. Mounting evidence suggests that Stat3 and related pathways may serve as a target for changing the tumour immunologic microenvironment to benefit cancer immunotherapies. Many recent studies support the use of certain tyrosine kinase inhibitors, through inhibition of STAT3, in decreasing immunosuppression in the tumour microenvironment. Other potential therapeutic avenues include the use of targeted delivery of Stat3 siRNA into immune cells.
Lee, Hh., Pal, S.K., Reckamp, K., Figlin, R.A. & Yu. H. STAT3: A Target to Enhance Antitumor Immune Response. 2010 Jun Current topics in microbiology and immunology. PMID: 20517723

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