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Tumor cell‐derived TGF‐β and IL‐10 dysregulate paclitaxel‐induced macrophage activation
Author(s) -
Mullins David W.,
Martins Ryan S.,
Burger Carol J.,
Elgert Klaus D.
Publication year - 2001
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.69.1.129
Subject(s) - paclitaxel , tumor necrosis factor alpha , biology , tumor microenvironment , cancer research , macrophage , nitric oxide , transforming growth factor , proinflammatory cytokine , cytotoxic t cell , immunotherapy , immune system , inflammation , immunology , microbiology and biotechnology , in vitro , endocrinology , cancer , biochemistry , genetics
Paclitaxel (TAXOL™) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL‐12, tumor necrosis factor α (TNF‐α), and nitric oxide (NO). However, tumors dysregulate Mø through soluble suppressor molecules, and it is possible that tumors evade paclitaxel‐mediated immune effector function through the production of immunomodulatory molecules and inhibition of Mø function in situ . Because Mø activation in the tumor microenvironment is a desirable goal of anti‐tumor immunotherapy, we evaluated whether tumor‐derived immunomodulatory factors dysregulate paclitaxel‐mediated Mø activation. Tumor cell‐derived supernatant suppressed paclitaxel's capacity to induce IL‐12, TNF‐α, and NO production by RAW264.7 Mø. Tumor factors also dysregulated paclitaxel‐induced expression of a HIV‐LTR, promoter‐driven luciferase construct in RAW264.7 Mø, suggesting that tumors may inhibit a broad range of Mø functionality. Depletion studies revealed that IL‐10 and transforming growth factor‐β 1 (TGF‐β 1 ), but not prostaglandin E 2 (PGE 2 ), impaired paclitaxel‐mediated activation, suggesting that abrogation of these factors in situ might restore paclitaxel's activating capacity and enhance anti‐tumor efficacy.