Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
As also discussed above, infiltrating cells of the immune system are increasingly accepted to be generic constituents of tumors. These inflammatory cells operate in conflicting ways: both tumor-antagonizing and tumor-promoting leukocytes can be found, in various proportions, in most if not all neoplastic lesions. Although the presence of tumor-antagonizing CTLs and NK cells is not surprising, the prevalence of immune cells that functionally enhance hallmark capabilities was largely unanticipated. Evidence began to accumulate in the late 1990s that the infiltration of neoplastic tissues by cells of the immune system serves, perhaps counterintuitively, to promote tumor progression. Such work traced its conceptual roots back to the association of sites of chronic inflammation with tumor formation, and to the observation that tumors could be portrayed as wounds that never heal. In the course of normal wound healing and fighting infections, immune inflammatory cells appear transiently and then disappear, in contrast to their persistence in sites of chronic inflammation, where their presence has been associated with various tissue pathologies, including fibrosis, aberrant angiogenesis, and neoplasia.
Over the past decade, the manipulation of genes involved in the determination or effector functions of various immune cell types, together with pharmacological inhibitors of such cells or their functions, has shown them to play diverse and critical roles in fostering tumorigenesis. The roster of tumor-promoting inflammatory cells now includes macrophage subtypes, mast cells, and neutrophils, as well as T and B lymphocytes. Such studies are yielding a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the tumor growth factor EGF, the angiogenic growth factor VEGF, other proangiogenic factors such as FGF2, chemokines, and cytokines that amplify the inflammatory state; in addition, these cells may produce proangiogenic and/or proinvasive matrix-degrading enzymes, including MMP-9 and other matrix metalloproteinases, cysteine cathepsin proteases, and heparanase. Consistent with their expression of these diverse effectors, tumor-infiltrating inflammatory cells have been shown to induce and help sustain tumor angiogenesis, to stimulate cancer cell proliferation, to facilitate, via their presence at the margins of tumors, tissue invasion, and to support the metastatic dissemination and seeding of cancer cells.
In addition to fully differentiated immune cells present in tumor stroma, a variety of partially differentiated myeloid progenitors have been identified in tumors. Such cells represent intermediaries between circulating cells of bone marrow origin and the differentiated immune cells typically found in normal and inflamed tissues. Importantly, these progenitors, like their more differentiated derivatives, have demonstrable tumor-promoting activity. Of particular interest, a class of tumor-infiltrating myeloid cells (defined as coexpressing the macrophage marker CD11b and the neutrophil marker Gr1) has been shown to suppress CTL and NK cell activity, having been independently identified as MDSCs. This attribute raises the possibility that recruitment of certain myeloid cells may be doubly beneficial for the developing tumor, by directly promoting angiogenesis and tumor progression while at the same time affording a means to evade immune destruction.
The counterintuitive existence of both tumor-promoting and tumor-antagonizing immune cells can be rationalized by invoking the diverse roles of the immune system: On the one hand, the immune system specifically detects and targets infectious agents with the adaptive immune response, which is supported by cells of the innate immune system. On the other, the innate immune system is involved in wound healing and clearing dead cells and cellular debris. These specialized tasks are accomplished by distinct subclasses of inflammatory cells, namely a class of conventional macrophages and neutrophils (engaged in supporting adaptive immunity), and subclasses of “alternatively activated” macrophages, neutrophils, and myeloid progenitors that are engaged in wound healing and tissue housecleaning. The latter subtypes of immune cells are one of the major sources of the angiogenic, epithelial, and stromal growth factors and matrix-remodeling enzymes that are needed for wound healing, and it is these cells that are recruited and subverted to support neoplastic progression. Similarly, subclasses of B and T lymphocytes may facilitate the recruitment, activation, and persistence of such wound-healing and tumor-promoting macrophages and neutrophils. Of course, other subclasses of B and T lymphocytes and innate immune cell types can mount demonstrable tumor-killing responses. The balance between the conflicting inflammatory responses in tumors is likely to prove instrumental in prognosis and, quite possibly, in therapies designed to redirect these cells toward tumor destruction.