Tumor cell-derived TGF-beta and IL-10 dysregulate paclitaxel-induced macrophage activation.
Paclitaxel (TAXOL) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL-12, tumor necrosis factor alpha (TNF-alpha), 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 microenviroment 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-alpha, 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-beta1 (TGF-beta1), but not prostaglandin E2 (PGE2), impaired paclitaxel-mediated activation, suggesting that abrogation of these factors in situ might restore paclitaxel's activating capacity and enhance anti-tumor efficacy.
Mullins
D W
DW
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA. dmullins@virginia.edu
Martins
R S
RS
Burger
C J
CJ
Elgert
K D
KD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000276:immunology / Q000494:pharmacology*; D015536:Down-Regulation; D004347:Drug Interactions; D016753:Interleukin-10 / Q000276:immunology* / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D017239:Paclitaxel / Q000276:immunology / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D017239:Paclitaxel