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Late-stage tumor environment facilitates T cell apoptosis

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Tumor-infiltrating T lymphocytes (TIL) that fight malignancies early in their development later lose their tumor-fighting capacity. Now, researchers report that the tumor environment itself induces TIL defects that sap them of their antitumor immunity and causes them to undergo cell death.

This phenomenon appears to explain why cancer vaccines are effective only against early-stage tumors, Dr. Christopher J. Wheeler and colleagues at Cedars Sinai Medical Center in Los Angeles report in the February 1st issue of The Journal of Immunology. They hope these findings will translate into new ways to augment endogenous or induced antitumor immunity.Using gliomas and melanomas grown in mice, the authors found that as tumors progress, TIL increasingly harbor an unusual “double negative” phenotype, in which the cells no longer express CD4 and CD8 receptors. At the same time, apoptotic markers and multiple molecular signaling defects are expressed. Other characteristics of the double negative TIL cells include deficient self-MHC class I expression, reduced interleukin-2 (IL-2), and production of intracytoplasmic IL-10, a cytokine known to inhibit T cell function and promote tumor progression.After the authors transferred na?ve CD8 T cells into wild-type melanomas, these cells lost their CD8 expression within 48 hours, supporting their hypothesis that the local tumor environment is sufficient to confer the double negative TIL phenotype to na?ve CD8 T cell.”What we envisage [to increase antitumor activity] is a kind of combinatorial treatment where we systemically activate the immune system, and also block or inhibit the local barriers to antitumor immunity at the tumor level,” Dr. Wheeler told Reuters Health.For example, he said, his team is considering “delivery of cells with MHC1 class competence to enhance survival of T cells, combined with systemic vaccination.”There are a number of ways this might be accomplished, co-author Dr. Keith L. Black added, including “direct injection at the time of surgery.” Other paths are selective intravascular delivery that can cross the blood tumor barrier and convection-enhanced delivery.(Source: J Immunol 2004;172:1602-1611: Reuters Health: Karla Gale: January 29, 2004: Oncolink)


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Posted On: 30 January, 2004
Modified On: 3 December, 2013

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