Abstract
Background. Impaired T-cell function has been noted in tumor-infiltrating lymphocytes (TIL).
Recently, loss of function was found to be associated with modifications in T-cell
receptor complex (TCR)-mediated signaling. A common feature is loss or reduced expression
levels of the signaling chain, TCRζ. We evaluated whether loss of function in TIL
and tumor-associated lymphocytes (TAL) from patients with ovarian cancer is associated
with changes in TCRζ expression, and which factors can cause these defects. Methods. TIL and TAL were isolated from multiple patients and evaluated for their proliferative
capacity by stimulation with a polyclonal stimulus. In addition, expression of TCRζ
and CD3ϵ was evaluated in fresh TIL and TAL by the Western blot technique. Finally,
various conditions within a tumor environment were tested for their effect on TCRζ
and CD3ϵ. Results. TIL, but not TAL, were significantly impaired in their proliferative response, even
when both populations were derived from the same patient (P <.05). Reduced proliferation levels were associated with loss of expression of TCRζ
but not of CD3ϵ. Exposure of normal T cells to relative ischemia or heat shock, or
culture in medium without IL-2, did not significantly reduce expression of TCRζ compared
with CD3ϵ. However, coculture of T cells with tumor-derived macrophages or tumor-derived
factors led to a selective loss of TCRζ compared with CD3ϵ (P <.05). Further analysis suggested that oxides such as hydrogen peroxide secreted
by macrophages may be responsible for loss of TCRζ and high molecular weight factors
secreted by certain tumors. Conclusions. TIL but not TAL show impaired T-cell function, which is associated with loss of TCRζ.
In addition to macrophages secreting oxides, loss of TCRζ may be caused by tumor-derived
soluble factors. (Surgery 2001;129:749-56.)
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Article info
Publication history
Accepted:
January 19,
2001
Footnotes
*Supported by National Institutes of Health grants R01 CA60662 and T32 CA09535, and a grant from the Gillette Center for Women's Cancers of the Dana Farber Cancer Institute.
**Reprint requests: Peter S. Goedegebuure, PhD, Department of Surgery, Washington University School of Medicine, 660 S Euclid Ave, Box 8109, St. Louis, MO 63110.
★Surgery 2001;129:749-56.
Identification
Copyright
© 2001 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
