Reprogramming of TAM toward proimmunogenic type through regulation of MAP kinases using a redox-active copper chelate

TAMs, present in the tumor microenvironment, play an immunosuppressive role, leading to tumor progression and metastasis. Recently, numerous attempts have been made to switch immunosuppressive TAMs into an immunostimulatory type. Previously, we showed that a copper chelate, viz., copper N-(2-hydroxy acetophenone) glycinate [CuNG], can reprogram TAMs toward the proimmunogenic type to mount an antitumor immune response, but the underlying molecular mechanisms of skewing TAMs toward the proimmunogenic type remain elusive. Herein, we tried to explore the signaling mechanisms responsible for the reprogramming of TAMs. We observed that CuNG-induced ROS generation triggers activation of two MAPKs, i.e., p38MAPK and ERK1/2, and also causes up-regulation of intracellular glutathione. Furthermore, activation of p38 MAPK up-regulated the initial IL-12 production and the activation of ERK1/2 in tandem with GSH, found responsible for IFN-gamma production by TAMs. This IFN-gamma, in turn, prolonged IL-12 production and down-regulated TGF-beta production and thus, plays the decisive role in CuNG-mediated reprogramming of regulatory cytokine production by TAMs. Our work highlights that ROS-mediated activation of MAPKs can convert suppressive macrophages toward the proimmunogenic type. Thus, the present study opens the possibility of targeting TAMs by the use of redox-active compounds for designing a novel, therapeutic strategy against cancer. J. Leukoc. Biol. 91: 609-619; 2012.