By Charlotte O’Donnell PhD
Inflammation and Cancer
The link between inflammation and cancer is well established, with inflammation highlighted as one of the enabling characteristics in cancer development . As early as 1863, Virchow indicated that cancer tended to occur at sites of chronic inflammation. Indeed many cancers are associated with chronic inflammation. Patients with chronic hepatitis caused by Hepatitis B and C infection are at increased risk of developing hepatocellular carcinoma, while infection with human papilloma virus (HPV) is linked to the development of cervical cancer . In the colon, inflammatory bowel disease (IBD)-associated inflammation increases the risk of developing CRC. Inflammatory bowel diseases (IBDs) are inflammatory disorders of the gastrointestinal tract that can be subdivided into two major disorders: ulcerative colitis (UC) and Crohn’s disease (CD). Indeed, the extent and the duration of UC was found to directly correlate with the risk of CRC development . Mortality is also increased in patients who develop CRC following UC, suggesting that the inflammatory processes observed in this disease may result in a more aggressive tumour phenotype.
The Inflammatory Component of Tumours
Tumours are composed of both tumour cells and non-tumour cells, with the tumour microenvironment describing the non-cancerous cells present in the tumour. In this microenvironment tumour cells interact with surrounding cells, including cancer-associated fibroblasts, endothelial cells, adipocytes and immune cells. Immune cells present in the tumour microenvironment have been shown to have wide ranging effects. They can influence cellular proliferation signals, angiogenesis and tissue remodelling in ways that can either promote or suppress tumour progression (Figure 1).
Immune cells are recruited into the tumour microenvironment by soluble chemo-attractants produced by cancer cells and stromal cells . Chemokines are small (8-11 kDa), secreted proteins that regulate the number and the phenotype of immune cells recruited by tumours. However, chemokines can also be exploited by the tumour to promote tumour growth, survival, angiogenesis and tumour cell migration . For instance, the chemokine CXCL1 can function as both a growth factor for cancer cells and as an angiogenic factor that regulates angiogenesis, which is critical for tumour growth and progression.
Cytokines are low molecular weight protein mediators that facilitate cell-to-cell communication. Multiple cell types in the tumour microenvironment express these inflammatory mediators, including immune cells and stromal cells such as fibroblasts and endothelial cells. Cytokines perform numerous functions including the regulation of cellular proliferation, migration and cell death as well as immune cell activation. Depending on the tumour microenvironment, cytokines can promote a pro- or anti-tumour immune response. This is dependent on a number of factors, including the balance of pro- and anti-inflammatory cytokines, their comparative concentrations and cytokine receptor expression by the immune cells .
Figure 1: Tumour-infiltrating immune cells and tumorigenesis. Upon recruitment to tumours, immune cells are exposed to various tumour- or immune-derived factors. These factors can skew the function of the immune cell towards an anti-tumour or pro-tumour response. Immune cells associated with pro-tumour activities include M2 macrophages, N2 neutrophils, myeloid-derived suppressor cells (MDSCs) and T-reg cells. Immune cells associated with tumour rejection include M1 macrophages and N1 neutrophils. Anti-tumour activity is also displayed by various lymphocyte subsets, such as NK cells, CD8+ T cells, γδ1 T cells and Th1 cells. These leukocytes are usually cytotoxic and produce cytokines that can promote tumour rejection.
Tumour associated Macrophages
Macrophages are key components of the immune infiltrate found in tumours . Two main macrophage phenotypes have been identified (Figure 2). Classically activated M1 macrophages are regarded as anti-tumorigenic, while M2 macrophages are pro-tumorigenic (Figure 2) . M1 macrophages can stimulate an anti-tumour immune response via production of pro-inflammatory cytokines such as IL-12, IL-23 and TNFα. M2 macrophages promote an immunosuppressive microenvironment by production of cytokines such as IL-10, can be immunosuppressive and inhibit the activity of Th1 cells and NK cells. Moreover, this immune suppressed environment can be exploited by the tumour to invade surrounding tissue and metastasize to distant organs .
M1 and M2 chemokine profiles can vary significantly, resulting in the recruitment of distinct immune cells. M1 macrophages are known to chiefly produce CXCL9 and CXCL10, which are chemotactic factors for T-helper 1 (Th1) and cytotoxic T-cells (CTLs), while M2 macrophages mainly secrete CCL17 and CCL22, which recruit regulatory T cells (T-reg) and T-helper type (Th2) subsets . Studies have shown that tumour associate macrophages (TAMs) are phenotypically more like M2 macrophages . M2 TAMs can contribute to tumorigenesis through several mechanisms, such as release of PGE2 and IL-10 which suppresses the anti-tumour immune response. Alternatively activated TAMs facilitate tumour growth by secreting pro-angiogenic factors. Although TAMs are predominantly associated with poor prognosis in many cancers, the role of TAMs in CRC still remains unclear. Indeed, numerous studies have shown that TAMs can positively influence CRC patient survival .
Figure 2: M1 versus M2 macrophages in tumorigenesis. Upon recruitment to the tumour, macrophages are exposed to factors derived from the tumour microenvironment that can skew their function. TAMs polarized towards an M1 phenotype play a vital role in tumour rejection, while TAMs polarized towards an M2 phenotype can drive tumour progression. M1 macrophages stimulate a tumour suppressing response via production of immunosuppressive cytokines, such as IL-1, IL-12 and TNFα. M2 macrophages activate a tumour promoting response by promoting angiogenesis, metastasis and invasion via a Th2 response. M2-polarized macrophages also produce potent pro-survival molecules. These molecules regulate gene expression in neoplastic cells by altering cell-cycle progression and increasing tumour cell survival. Together these processes circumvent immuno-surveillance and tumour-reactive immunity.
Tumour associated Neutrophils
Although not as well studied as TAMs, tumour associated neutrophils (TANs) can have either a pro-tumorigenic (N1) or an anti-tumorigenic (N2) phenotype. N1 neutrophils are cytotoxic to tumour cells and express increased levels of the pro-inflammatory cytokines IL-12, VEGF, TNF-α, and IL-1β. N1 TANS also produce tumouricidal factors such as proteases, while N2-neutrophils secrete arginase to suppress T cell effector functions, comparable to M2 like TAMs. N2 TANS can also influence angiogenesis  through the production of mediators such as oncostatin M, which stimulate the production of VEGF by malignant cells.
Myeloid-Derived Suppressor Cells
Myeloid-derived suppressor cells (MDSCs) are CD11b+Gr1+ immature myeloid cells that have been shown to be capable of suppressing immune responses. In addition, these cells become pathologically activated and can directly support tumour progression. MDSCs suppress immune function in a number of ways including the expression of arginase, inducible NOS (iNOS) and COX2 .
Tumour infiltrating Lymphocytes
Low numbers of lymphocytes are found in tumours, these cells predominantly localize to the invasive margin . T cells can express either CD8 glycoprotein and are called CD8+ T cells (cytotoxic) or CD4 glycoprotein and are called CD4 cells, but are also known as T helper (Th) cells. The two main subsets of CD4+ cells are Th1 and Th2 cells. These cells differ in their cytokine secretion patterns and functions. Th1 cells are involved in the maturation of B cells and the activation of macrophages. Th2 cells play a key role in immunological tolerance. Although both CD4+ and CD8+ T cells can infiltrate tumours, CD4+ T-cells are unable to recognise cancer cells directly , as opposed to CD8+ T cells, which can directly kill cancer cells. Indeed, intraepithelial CD8+ TILs were found to be a positive predictor of survival in CRC. Similarly low CD8+ T cell infiltration is indicative of therapy resistance and poor prognosis in many human malignancies [ 15].
Regulatory T cells
Regulatory T cells (T-regs) are CD4+CD25+Foxp3+ cells involved in maintaining self-tolerance. One of the ways in which they promote immune suppression in CRC is through production of TGF-β and IL-10. TGF-β can directly suppress effector T cell signalling . However, the role of T reg cells in CRC is controversial as numerous studies have shown that increased T reg cells are indicative of an improved prognosis.
Natural Killer Cells
Natural killer (NK) cells are cytotoxic cells that target and kill both virally infected cells and cancer cells. NK cells initiate the innate immune response and can promote powerful anti-tumour cytotoxicity in vitro. Their cytotoxicity is dependent on the level of activation of the NK cells by the presence of surface markers, as tumours express both activating and inhibiting receptors. Transformed cells may express reduced levels of MHC class I molecules in combination with other ligands. This enables them to evade being targeted by CD8+ T cells and CTLs. However, this makes them more vulnerable to attack by NK cells .
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