Immune Suppression and Colorectal Cancer

C. Evans; A. G. Dalgleish; D. Kumar

Disclosures

Aliment Pharmacol Ther. 2006;24(8):1163-1177. 

In This Article

Shift in TH1/TH2 Immune Responses

Immune responses may be broadly divided into cell-mediated immunity (CMI) and humoral immunity (HI). CMI is associated with TH1 CD4+ T lymphocytes producing cytokines IL-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. In contrast HI is associated with TH2 CD4+ T lymphocytes producing IL-4, IL-6 and IL-10.[41] Immune deviation towards TH1 responses results in tumour rejection as TH1 pathways typically produce activation of cytotoxic T-cell lymphocytes (CTL), natural killer (NK) cells, macrophages and monocytes, all of which can attack cancer cells and generally defend against tumours.[42] Conversely deviation towards TH2 response prevents tumour rejection.[43,44] Almost all malignancies are associated with suppression of the CMI.[41]

A shift in immune function has been demonstrated in patients with colorectal cancer. Decreased total numbers of TH1 CD4+ cells have been found in patients with colorectal tumours[45] and there is reduced production of cytokines from TH1 lymphocytes whilst those produced by TH2 lymphocytes appear to remain at normal or even elevated levels.[38,46,47,48,49] The further the disease process has progressed the more significant these imbalances become[38,47,48,49,50] with levels of the HI-associated cytokines having a prognostic influence in terms of disease-free survival and tumour recurrence postsurgery.[39]

An explanation for this shift in immunity is that the majority of colorectal cancer evolves in a chronic inflammatory background; the precursor lesions, whether adenomas or polyps, are often inflammatory in nature.[51] Chronic inflammation exhibits the immunology of wound healing in which CMI is suppressed and both HI and angiogenic growth factors are abundant. This is to prevent the immune system from destroying newly repaired tissue which expresses new epitopes.[52] Thus, having evolved in an immune suppressed state it is not surprising that in order to grow and metastases colorectal tumours have to mimic their original environment. The mechanisms by which the tumours evoke this shift in host immunity have not been completely explained; however, several different factors have been implicated.

Cyclo-oxygenase (COX) is a rate-limiting enzyme for the synthesis of eicosanoids, such as prostaglandins, from arachidionic acid and overexpression of its inducible form (COX-2) is a central event in colorectal cancer carcinogenesis[53] occurring in 80% of colorectal tumours.[54] Five mechanisms have been identified by which COX-2 contributes to tumorigenesis, including: (i) inhibition of apoptosis; (ii) increased angiogenesis; (iii) increased invasiveness; (iv) conversion of procarcinogens to carcinogens and (v) modulation of inflammation/immunosuppression.[55]

TH2 cytokines, such as IL-14 and IL-10, which downregulate the proinflammatory state and inhibit the synthesis of TH1 cytokines by CD4+ T- helper lymphocytes, are produced in COX-2 environments.[56] Prostaglandin E2 is produced by colon carcinoma cells expressing COX-2 and reduces the activation of NK cells and CTL cells, causing inhibition of IL-2 production and downregulation of IL-2 receptor expression on the effector surface.[57] Thus, COX-2 overexpression leads to a downregulation of the CMI response and promotion of HI.

Exposure to COX inhibitory drugs [aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS)] is associated with a reduced risk for developing colon cancer.[53] However, recent study suggests that COX-2 expression does not seem to be related to the survival of colorectal cancer patients and other potential targets, such as the peroxisome proliferator-activated receptors, might be modulating the production of the protective effect of NSAIDS.[58]

Endogenous histamine synthesis in tumour tissues suppresses local tumour immunity and promotes tumour growth.[59] Histamine deregulates the balance between TH1 and TH2 cells,[60] enhancing secretion of TH2 cytokines, such as IL-4, IL-5, IL-10 and IL-13 whist inhibiting production of TH1 cytokines IL-2 and IFN-γ and monokine IL-12.[61,62] Its inhibition of CMI is mediated through a number of mechanisms: (i) histamine increases intracellular cyclic AMP (cAMP) which inhibits IL-2 formation in T cells through protein kinase A activation. IFN-γ formation is concomitantly decreased, and thus CMI attenuated.[63] (ii) Histamine stimulates DC to differentiate into Th2 cell-promoting effector DC (DC2) which promotes a TH2 response.[64]

Upregulation of histamine and histidine decarboxylase (the enzyme that catalyses the decarboxylation of histidine to histamine) occurs in colorectal cancers and correlates with the tumour stage.[65] The levels measured are in high enough concentrations to be locally immunosuppressive.[66]Exogenous histamine administered to mice implanted with colon 38 mouse colon adenocarcinoma resulted in stimulated cancer growth with attenuation of antitumour cytokine expression within the tumour microenvironment.[60] The histamine (H2) receptor antagonists famotidine enhances lymphocytic infiltration in colorectal cancer[67] and cimetidine attenuates experimental tumour growth.[68] However, whilst some studies have found survival benefits in the administration of H2 receptor antagonists[69,70] others have shown no significant change in colon cancer death rates[71] and more recent studies suggest that beneficial effects may be the result of a blockade of histamine's stimulation of angiogenesis [mediated via the release of vascular endothelial growth factor (VEGF)][72,73] or inhibiting adhesion between endothelial cells and colorectal cancer cells.[74]

Interleukin-10 is a TH2 type pleiotropic cytokine[75] able to limit and ultimately terminate inflammatory responses[76] and skew the immune response from TH1 to TH2.[77] It inhibits the production of TH1 cytokines from TH1 cells,[78] DC stimulation of TH1 cell IFN-γ production, APC B7 expression and antigen presentation to TH1 cells whilst inducing IL-1 receptor antagonist production in neutrophils.[77] It mediates tumour cell resistance to CTL killing,[79,80] suppresses CTL development and blocks TH0 cell differentiation to TH1 cells.[81] It may also suppress T CMI by downregulating the function of TAP molecules and the expression of MHC class I molecules on target cells.[82]

Many malignant diseases overexpress IL-10 including: melanoma,[83] basal cell and squamous carcinoma,[84] renal cell carcinoma[85] and colorectal cancer.[39,47,75,86] Colorectal tumour cells are able to secrete IL-10 directly,[87] or indirectly.[88] Carcinoembryonic antigen (CEA) induces the release of IL-10[89] plus tumour cells are able to enhance the ability of monocytes and intestinal macrophages to produce IL-10.[90]

Elevated serum levels of IL-10 have been described as a negative prognostic factor for responsiveness towards treatment, as well as the disease-free and overall survival for patients with colorectal cancer.[91] IL-10 serum levels returned to normal in radically resected patients whilst persistently elevated IL-10 serum levels after surgery predicted tumour recurrence[92,93] and a further significant increase in IL-10 serum levels was observed in non-responders after chemotherapy.[94]

There is still controversy over IL-10's involvement as some experimental studies have shown profound inhibition of tumour establishment, growth and metastasis by IL-10.[95] Adris et al.[96] demonstrated IL-10 able to recruit and activate a T cell-mediated antitumour response against murine CT26 colon carcinoma cells within the context of a shift towards a Th2 immunity. IL-10's effects on cancer appear to be diverse, largely dependent on the experimental model and the immunological background milieu which in turn can be determined by genetic factors.[91]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....