Gender dimorphism of macrophage response to GMCSF and IL-4 for differentiation into dendritic cells

We previously demonstrated the existence of gender dimorphism in a murine tumor model with respect to the growth of a spontaneous T-cell lymphoma designated as Dalton's lymphoma and several aspects of host-tumor interaction. We also demonstrated the involvement of macrophages in manifestation of gender-dependent differential tumor growth [J Reprod Immunol 2005; 65:17, Cancer Invest 2006; 24:1, J Biomed Sci 2007 (in press), J Reprod Immunol 2007; 74:90]. Although monocytes/macrophages of tumor-bearing hosts have been used to differentiate into macrophage-derived dendritic cells for various applications in the immunotherapy of cancer, it remains unclear if macrophages show a gender-dependent differential response to the signals of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for differentiation to cells with dendritic cell morphology (MO-DC) and if these MO-DC have a gender-dependent differential therapeutic efficacy in inhibiting tumor growth.

Peritoneal macrophage obtained from male and female mice were incubated in vitro for a period of 7 days in a medium containing GM-CSF (800 IU/mL) and IL-4 (500 IU/mL) followed by incubation for further 24 hr in medium alone or containing lipopolysaccharide (LPS; 10 ng/mL) to differentiate into cells with DC morphology (MO-DC). The MO-DC thus obtained were used to check a variety of phenotypic and functional parameters related to their gender-dependent anti-tumor activity.

The MO-DC obtained from male mice showed a better response to GM-CSF and IL-4 treatment and activation by LPS for differentiating into cells with DC phenotype compared with that of female mice. MO-DC of male mice showed a comparatively higher tumoricidal activity, expression of DC markers [chemokine receptor-5 (CCR-5), ICAM-1 (CD-54) and CD-80], MLR, pinocytosis and production of NO, IFN-gamma and TNF-alpha. Adoptive transfer of MO-DC obtained from male mice to tumor-bearing mice resulted in a longer prolongation of survival duration and a better retardation of tumor growth compared with the MO-DC obtained from female mice.

To the best of our knowledge, this is the first report of its kind to demonstrate the existence of gender dimorphism in the antitumor and other accessory functions of macrophages differentiated in vitro into cells with DC morphology. These observations may have long lasting clinical significance in developing gender-specific protocols regarding the use of MO-DC in cancer immunotherapy.