The Tumor Microenvironment Is Toxic to T Cells

Tumors are known to express "tumor-rejection" antigens, and T cells specific for these tumor antigens are present either in the circulation or within tumors. If circulating T cells become activated and extravasate into the tumor parenchyma, they often encounter immunosuppressive molecules either secreted by or expressed on the surface of the tumor cells. For example, B7-H1, a member of the B7 family of costimulatory molecules, can be expressed by carcinomas and result in the induction of apoptosis of activated T cells.135 Also, many tumors are known to secrete transforming growth factor (TGF)-b, or IL-10,136 two cytokines known to down-modulate T-cell function. Regulatory T cells that function to suppress Th1 immune responses normally secrete both these cytokines.137,138 Ectopic secretion of those cytokines by tumor cells can suppress Th1 cell-mediated rejection of tumors.

Blocking tumor-specific B7-H1 molecules from binding to their ligands on activated T cells improved the efficacy of antitumor T cells in preclinical models,139,140 suggesting a therapeutic approach. IL-2 at high doses produces significant clinical responses in some cancers and is being tested in combination with tumor vaccines.59,60 The B7-H1-mediated negative effect on T-cell function is overcome in the presence of exogenous IL-2.64 A very low dose IL-2 regimen has been shown to result in the prolonged persistence of transferred T cells in melanoma patients.65 This dose of IL-2 is sufficient to saturate IL-2 receptors in vivo.141 Therefore an "immune augmenting" effect of IL-2 can potentially be achieved with minimal toxicity.

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