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Journal of Lipid Research, Vol. 46, 1983-1990, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing

Alan M. Kleinfeld¹ and Clifford Okada

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Published, JLR Papers in Press, June 16, 2005. DOI 10.1194/jlr.M500151-JLR200

¹ To whom correspondence should be addressed. e-mail: akleinfeld{at}tpims.org

Immune-mediated antitumor activities confront a variety of tumor-mediated defense mechanisms. Here, we describe a new mechanism involving FFA that may allow breast cancer to evade immune clearance. We determined the IC₅₀ at which unbound free fatty acids (FFA_u) inhibit murine cytotoxic T-lymphocyte (CTL)-mediated killing to assess the physiologic relevance of this phenomenon. We found that the IC₅₀ for unbound oleate is 125 ± 30 nM, 200-fold greater than normal plasma levels. FFA inhibition, however, may play an important role in breast cancer because we found that large quantities of FFAs are released constitutively into the media surrounding samples of human breast cancer but not normal or benign tissue. FFA_u concentration ([FFA_u]) increased to at least 25 nM in 20 of 22 cancer tissue samples and exceeded 100 nM in 11 patients. Media from these samples inhibited CTL-mediated killing. Extrapolation from our in vitro conditions suggests that for tumor interstitial fluid, in vivo [FFA_u] may be 300-fold greater than we observed in vitro.

Although breast cancer release of FFA may suppress effector cell antitumor activity, strategies that reduce interstitial [FFA_u] may significantly improve antitumor immune therapies.

Abbreviations: ADIFAB, acrylodan-labeled intestinal fatty acid binding protein; CHTN, Cooperative Human Tissue Network; CTL, cytotoxic T-lymphocyte; FAFBSA, fatty acid-free bovine serum albumin; FCS, fetal calf serum; FFA_u, unbound free fatty acids; [FFA_u], unbound free fatty acid concentration; OA_u, unbound oleate concentration

Supplementary key words unbound free fatty acid • free fatty acid release • immunotherapy

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