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Memory T cells in human tumor and chronic inflammatory microenvironments: sleeping beauties re-awakened by a cytokine kiss.

Abstract：

:Human tumors often progress and spread in spite of the presence of large numbers of CD4+ and CD8+ T cells with activated or memory cell phenotypes. The T cells in the microenvironment of human lung tumors fail to be activated in response to stimulation via the T cell receptor and CD28 under conditions that fully activate T cells derived from the peripheral blood of the cancer patients. A combination of regulatory mechanisms which are also observed in a variety of different chronic inflammatory conditions may contribute to the T cell unresponsiveness, and to their inability to respond to and kill tumor cells. The non-responsiveness of memory T cells isolated from human lung tumors and non-malignant chronic inflammatory tissues can be reversed in vitro by a brief pulse with IL-12, and the local and sustained release of exogenous IL-12 into the microenvironment of human tumor xenografts in SCID mice re-activates the tumor-associated T cells in situ. In the later case, the T cells proliferate, secrete interferon-gamma and initiate a cascade of events that culminate in the eradication of tumor cells from the xenograft. In transplantable and spontaneously developing tumors of mice the injection of a single tumor nodule with IL-12 loaded biodegradable microspheres activates tumor-associated T cells to kill tumor cells in situ, and provokes a systemic anti-tumor response that results in the eradication of distant metastatic tumor nodules that are not treated with the cytokine. These mice exhibit a systemic tumor specific immunity as they resist a second challenge with the same (but not a different) tumor. These findings suggest that it will be possible to provoke a systemic anti-tumor immunity in cancer patients by the direct injection of IL-12 loaded biodegradable microspheres or liposomes to locally deliver very low but sustained doses of IL-12 into a single tumor site. This strategy which is based upon the ability of IL-12 to re-activate tumor-associated T cells is termed in situ tumor vaccination.

journal_name

Immunol Invest

journal_title

Immunological investigations

authors

Broderick L,Bankert RB

doi

10.1080/08820130600755066

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

419-36

issue

3-4

eissn

0882-0139

issn

1532-4311

pii

XM6T666X08308GV1

journal_volume

pub_type

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Memory T cells in human tumor and chronic inflammatory microenvironments: sleeping beauties re-awakened by a cytokine kiss.