Hsp70 induces Th1 polarization through tumor-associated macrophages in a T-cell lymphoma.

Abstract

Tumor progression produces immunoregulatory phenotype of macrophages in tumor bearing host (TBH), that mediate immunosuppression through increased production of soluble factors. These factors obviously suppress the T-cell responsiveness and underproduction of Th1-polarizing cytokines. Here, we reported that in vitro treatment of TAMs with autologous Hsp70 purified from DL-bearing mice reverse back the tumor induced macrophage suppressor activity, suggesting that Hsp70 can restore TAMs production of Th1-polarizing cytokines. LPS stimulation failed to overcome tumor-induced dysregulation of IL-1, IL-12, IL-15 and IFN-gamma production. In contrary, Hsp70 significantly enhanced IL12, IL-15, IL-1 and IFN-gamma production by TAMs in vitro and in vivo, but also enhanced the LPS and IFN-gamma responsiveness of TAMs. These Th1 polarizing effects of cytokines of TAMs are dose dependent and reach the maximal values at 24 hrs of incubation. Though, we found a significant release of IFN-gamma in TAMs without T-cells, and increased level of IFN-gamma with T-cells suggests that Hsp70 stimulates T-cells. Summarizing, these data demonstrates that Hsp70 restore Th1 polarizing cytokines production in the TBH and thus ascribe a possibility to develop a novel immunotherapeutic regime by using TAMs that could contribute well to the correction of tumor induced immune dysfunction.