Submitted on April 19, 2005
Revised on June 9, 2005
Accepted on June 15, 2005
Free fatty acid release from human breast cancer tissue inhibits cytotoxic T lymphocyte- mediated killing
Alan M. Kleinfeld and Clifford Okada
Membrane Biology, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121
Corresponding Author: akleinfeld{at}tpims.org
Immune-mediated anti-tumor 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 FFA (FFAu) inhibit murine cytotoxic T lymphocyte (CTL)-mediated killing, to assess the physiologic relevance of this phenomenon. We find that the IC50 for unbound oleate is 125 ± 30 nM, about 200 fold larger than normal plasma levels. FFA inhibition may, however, play an important role in breast cancer because we find that large quantities of FFA are released constitutively into the media surrounding samples of human breast cancer but not normal or benign tissue. [FFAu] rose 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-killing. Extrapolation from our in vitro conditions suggests that for tumor interstitial fluid in vivo [FFAu] may be 300 fold larger than we observe in vitro. Although breast cancer release of FFA may suppress effector cell anti-tumor activity, strategies that reduce interstitial [FFAu] may significantly improve anti-tumor immune therapies.
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