Immune Suppression and Colorectal Cancer

Regulatory T Cells

Regulatory T (T_reg) 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]

T_reg 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 T_reg cells in the peripheral blood of 42 patients with malignant tumours (nine of whom had colorectal cancer).^[206] High levels of T_reg cells have been identified in lung, ovarian, breast and pancreatic tumour specimens.^[197] T_reg 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 T_reg cells^[208] plus tumour-specific CD4⁺ T cells which emerge in the absence of T_reg cells are able to reject CT26 colon cancer cells.^[209]

T_reg 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 T_reg 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 T_reg cells.^[211]

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