Inflammation, Macrophage Differentiation, and Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Macrophages are chief participants in host inflammatory responses of the innate immune system. The capability of macrophages to have distinct functional phenotypes is typically manifested in pathological conditions including cancer. Macrophages have been shown to have the characterization of plasticity and polarization and can be both anti-tumorigenic (M1) and tumor promoting (M2). For instance, when GM-CSF-differentiated human macrophages are engaged with bacterial products and Th1 cytokines such as lipopolysaccharide (LPS) and interferon, they are polarized to classically activated macrophages, known as M1 macrophages, which have immune-stimulatory properties and cytotoxic function against tumor cells. While M-CSF-differentiated human macrophages are activated by Th2 cytokines such as IL-4 or immune-suppressors such as IL-10, they will become alternatively activated M2 macrophages, which have low cytotoxic functions but high tissue-remodeling activity. M1 and M2 macrophages have distinct chemokine profiles that lead to the recruitment of different subsets of immune cells. The molecular processes that occur during monocyte/macrophage differentiation and polarization, particularly in the differentiation of M2 type macrophage under pathological conditions such as cancer, are not completely understood. Tumor-associated macrophages (TAMs), the M2-like macrophages that represent the major infiltrating immune component of neoplastic stroma, are critical mediators of tumor initiation, progression and metastasis . Blocking the functions of TAMs or eliminating TAMs can effectively block tumorigenesis. TAMs promote tumor cell growth by suppressing antitumor immunity and inducing angiogenesis. The phenotypic skewing of macrophages by cancer cells has been well-documented. Events and factors that lead to macrophage polarization are secretion of tumor-derived factors, hypoxia, necrosis and tissue damage, inflammation and immune cells. Given that there are cross-talks established between tumor microenvironments (TME) and macrophages that directly or indirectly influence the types of macrophages and their functions, we set out to better understand how tumor cells/TME promote macrophages to become TAMs. Understanding the regulations of TAM polarization by tumor cells/TME may lead to new strategies for treating malignant tumors. As we found that TAM population is reduced in MLKL KO tumors, we investigate the underlying mechanism of necroptosis-promoted M2-polarization of tumor infiltrating macrophages. We found that tumor necrosis/necroptosis-induced inflammation is critical for tumorigenesis. tumor cells secret certain proteins to mediate the differentiation of TAMs, which, in turn, promote tumor growth. We are evaluating the roles of these proteins on TAMs function in animal cancer models. Eventually, we will test if using neutralizing antibodies against these proteins will help to control tumor metastasis. We also collaborated with others to study the inflammation-promoting effect on tumor development. We found that macrophages play a critical role in host "cytokine storm response" and thrombosis caused by viral infection. We recently found that necroptosis not only affects the anti-tumor activities of T cells, but also modulates macrophages' differentiation and functions. Recently we identified a novel soluble Tissue Factor (sTF), which is the key mediator of blood clotting, as the consequence of necroptosis in macrophages and tumor cells. Importantly, our data suggests sTF plays a key role in thrombosis under different pathological conditions including cancer, sepsis and viral infection. Our study suggests sTF is a novel diagnostic marker of thrombosis and a potential therapeutic target for treating the disease. To do so, we have developed a sTF specific humanized monoclonal antibody.