Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice

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 MΦ may be a novel strategy for drug development and immunotherapy.Macrophages (MΦ) represent the most abundant immune cell population in the tumor microenvironment and play a key role in tumor development [1,2]. High levels of MΦ infiltration into tumor tissues are associated with a poor prognosis; this is particularly true for hepatocellular carcinoma (HCC) [3-6]. Although a decreased number of macrophages correlates with a reduction in tumor growth in several tumor graft models [7,8], there are some exceptions. For example, depletion of Kupffer cells worsens the prognosis of tumor-bearing mice in peritoneal xenograft models because the cancer cells are able to metastasize to the liver; thus, the mice die from the increased tumor burden in the absence of MΦ [9,10]. These contradictory reports highlight the fact that little is known about the exact role of tumor-associated macrophages (TAMs) during tumor development.MΦ are a highly heterogeneous cell population. This is because their phenotypes and diverse functions are shaped by the tumor microenvironment [11]. MΦ can be classified on the basis of two distinct activation states. Classically activated MΦ (M1), induced by IFN-γ or microbial products, produce high levels of proinflammatory cytokines (IL-12 and IL-23), express major histocompatibility complex (MHC) molecules and i