Immune Suppression and Colorectal Cancer

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


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

In This Article

Regulatory T Cells

Regulatory T (Treg) cells are functionally defined as T cells that inhibit immune responses by influencing the activity of another cell type. They are a small subset (10%) of thymus-derived CD4+ T cells that co-express the CD25 antigen (the IL-2R α-chain) and control immune responses to autoantigens.[197] They are essential for immune system homeostasis[198] and play a critical role in the prevention of organ-specific autoimmunity and allograft rejection.[199] Their suppression of autoreactive T cells helps prevent autoimmune disorders[200,201,202] but also dampens antitumour responses by suppressing TAA-specific immunity.[203]

Treg cells suppress immune responses through the action of immunosuppressive cytokines (e.g. IL-10 and TNF-β) and/or via a cell contact.[204] They inhibit the proliferation and cytokine production of antigen-specific CD4+ or CD8+ T cells,[205] inhibit NK cell-mediated cytotoxicity,[206] and inhibit both DC maturation and antigen presenting function.[207]

Wolf et al. demonstrated a significant increase (2.5-fold) in Treg cells in the peripheral blood of 42 patients with malignant tumours (nine of whom had colorectal cancer).[206] High levels of Treg cells have been identified in lung, ovarian, breast and pancreatic tumour specimens.[197] Treg cells contribute to the growth of human tumours in vivo having been specifically recruited by both tumour cells and microenvironmental macrophages.[203] Rat colon cancer tumour volume is correlates with an expansion of Treg cells[208] plus tumour-specific CD4+ T cells which emerge in the absence of Treg cells are able to reject CT26 colon cancer cells.[209]

Treg cell depletion allows the immune system to mount an efficient antitumoural immune response against poorly immunogenic tumours[209] plus therapies which manipulate their regulatory mechanisms may evoke effective tumour immunity in otherwise non-responsive animals.[210] It may be that suppression of Treg cells allows other therapies to be more potent in their action. For example, a translational phase II trial investigating the treatment of colorectal carcinoma patients using combined chemo-immunotherapy [gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose IL-2] found a high objective response (68.9%) and disease control rates (96.5%) with an enhanced proliferative response to colon carcinoma antigen and a significant reduction in Treg cells.[211]


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