The tumor microenvironment at a glance

Cancers are not just masses of malignant cells but complex ‘rogue’ organs, to which many other cells are recruited and can be corrupted by the transformed cells. Interactions between malignant and non-transformed cells create the tumor microenvironment (TME). The non-malignant cells of the TME have a dynamic and often tumor-promoting function at all stages of carcinogenesis (Hanahan and Coussens, 2012). Intercellular communication is driven by a complex and dynamic network of cytokines, chemokines, growth factors, and inflammatory and matrix remodeling enzymes against a background of major perturbations to the physical and chemical properties of the tissue. The evolution, structure and activities of the cells in the TME have many parallels with the processes of wound healing and inflammation, but cells such as macrophages are also found in cancers that have no known association with chronic inflammatory conditions (Grivennikov et al., 2010; Hanahan and Weinberg, 2011; Mantovani et al., 2008). One reason for this is that inflammatory and wound-healing processes are activated downstream of oncogenic mutations in the malignant cells (Mantovani et al., 2008). This Cell Science at a Glance article will describe the functions of major non-malignant cell types that are found in the TME of most human and experimental cancers; the cells of the immune system, the tumor vasculature and lymphatics, as well as fibroblasts, pericytes and adipocytes, and will discuss their importance in cancer development, spread and response to treatment (see poster). The common features of many TMEs suggest that targeting the non-malignant cells, or mediators of their communication, have applications across different tumor types and could also complement other treatment options.Apart from malignant cells, the TME contains cells of the immune system, the tumor vasculature and lymphatics, as well as fibroblasts, pericytes and sometimes adipocytes, which are discussed in detail below. These cells are frequently distinguished by cell-type-specific markers, which are often cell surface molecules. An excellent summary of some of these is given by Joyce and Pollard (Joyce and Pollard, 2009), and some of the commonly used and most informative markers will be detailed below.There are many different T cell populations within the TME that infiltrate the tumor areas, at the invasive tumor margin and in draining lymphoid organs. Among these, cytotoxic CD8+ memory T cells (CD8+CD45RO+), which are normally antigen ‘experienced’ and capable of killing tumor cells, are strongly associated with a good prognosis (Fridman et al., 2012). CD8+ T cells are supported by CD4+ T helper 1 (TH1) cells, which are characterized by the production of the cytokines interleukin-2 (IL-2) and interferon gamma (IFN-γ); high numbers of these in the TME also correlate with a good prognosis (Fridman et al., 2012). Other CD4+ cell populations, such as TH2 cells producing IL-4, IL-5 and IL-13, which support B cell responses, or TH17 cells, producing IL-17A, IL-17F, IL-21 and IL-22 that favor anti-microbial tissue inflammation, are generally thought to promote tumor growth (Fridman et al., 2012), although they have also been associated with a favorable outcome, as in the case of TH2 cells in breast cancer (Yoon et al., 2010) and TH17 cells in esophageal cancers (Lv et al., 2011). The CD4+ T cells most often described as tumor promoting are the immunosuppressive T regulatory cells (Tregs), which are characterized by expression of FOXP3 and CD25 (Hsieh et al., 2012). Constitutive and induced Tregs exert an immune suppressive function through the production of IL-10, transforming growth factor beta (TGF-β) and cell-mediated contact through cytotoxic T-lymphocyte antigen 4 (CTLA4), inhibiting recognition and clearance of tumor cells by the immune system (Campbell and Koch, 2011). High numbers of Tregs in the TME correlate with worse prognosis in many types of cancer (Bates et al., 2006; Curiel et al., 2004; Hiraoka et al., 2006). Tregs can also be tumor suppressive as in some B cell cancers; their presence in Hodgkin's Lymphoma correlates with a good prognosis, presumably through a direct suppression of tumor cell growth (Fozza and Longinotti, 2011; Koreishi et al., 2010; Tzankov et al., 2008).γδ T lymphocytes have some characteristics of innate rather than adaptive immune cells and show potent cytotoxic activity against a wide range of malignant cells, including cancer stem cells (Gomes et al., 2010; Hannani et al., 2012). Although experimental animal cancer studies suggest they exert immune surveillance activity, it is not yet certain whether the presence of γδ T cells in the TME reflects a good or bad prognosis.B cells can be found at the invasive margin of tumors, but are more common in draining lymph nodes and lymphoid structures adjacent to the TME. B cell infiltration into the TME is associated with good prognosis in some breast and ovarian cancers (Coronella et al., 2001; Milne et al., 2009); however, this is in contrast to mouse models, in which B cells inhibit tumor-specific cytotoxic T cell responses (Qin et al., 1998). More recent data support a tumor-promoting role for B cells and immunoglobulin deposition in a genetic mouse model of skin cancer (Andreu et al., 2010; de Visser et al., 2005). An immunosuppressive population of IL-10-producing B cells, known as regulatory B cells (Bregs) or B10 cells (Mauri and Bosma, 2012), increases tumor burden and inhibits tumor-specific immune responses in inflammation-induced skin cancer (Schioppa et al., 2011), and also appear to favor lung metastasis in a mouse model of breast cancer (Olkhanud et al., 2011). Bregs also inhibit the clearance of tumor cells by anti-CD20 antibodies in a mouse model of lymphoma (Horikawa et al., 2011). However, none of these effects are due to Bregs infiltrating the TME; instead they appear to affect other immune cells in the surrounding lymphoid tissue or in the draining lymph nod