Effect Of Tumor-Associated Macrophages In Murine Hepatocellular Carcinoma Progression And Plasmodium Infection-Based Cancertherapy

Tumor-associated macrophages (TAMs) are the most abundant immune cells within the tumor stroma and play a crucial role in tumor development. Although clinical investigations indicate that high levels of macrophage (MΦ) infiltration into tumors are associated with a poor prognosis, the exact role played by TAMs during tumor development remains unclear. The present study aimed to investigate dynamic changes in TAM major histocompatibility complex (MHC) class II expression levels and to assess the effects of these changes on tumor progression. Significant inhibition of tumor growth in the murine hepatocellular carcinoma Hepa1-6 model was closely associated with partial TAM depletion. Strikingly, two distinct TAM subsets were found to coexist within the tumor microenvironment during Hepa1-6 tumor development. An MHC class IIhi TAM population appeared during the early phase of tumor development and was associated with tumor suppression; however, an MHC class IIlow TAM population became increasingly predominant as the tumor progressed. Tumor progression was positively correlated with increasing infiltration of the tumor tissues by MHC class IIlow TAMs. Thus, targeting the transition of MΦmay be a novel strategy for drug development and immunotherapy for cancer.Little is known about the effects of Plasmodium infection on cancer either in experimental or clinical settings. Here, we report that Plasmodium infection efficiently inhibited tumor progression and prolonged the average survival of tumor-bearing mice in a murine transplanted hepatoma model. The inhibition of tumor progression was associated with a decreased infiltration of tumor-associated macrophages (TAMs) and downregulation of MMP9 in TAMs, which ultimately resulted in the suppression of tumor angiogenesis. We further demonstrated that MMP9 expression dowregulation was associated with IGF-1 expression dowregulated by Plasmodium infection through the IGF-1R signaling via both the PI3-K and MAPK pathways in TAMs. Hemozoin, which accumulates in TAMs, plays an important role in the inhibition of angiogenesis by regulating IGF-1 expression. Elucidating the impact of Plasmodium infection on cancer pathogenesis is important for developing new therapeutic strategy for targeting tumors.