Immune Suppression and Colorectal Cancer

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

Disclosures

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

In This Article

Summary and Background

Background: Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth.
Aim: To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development.
Method: A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers.
Results: Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome.
Conclusions: Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.

Colorectal cancer is a common malignancy with annual incidence of over 945 000 cases worldwide and an annual mortality of 492 000.[1] Surgery is the treatment of choice offering a potential cure. However, 30–40% of patients have loco regionally advanced or metastatic disease on presentation which cannot be cured by surgery alone.[2] In addition, more than half of patients initially believed to be cured by surgery develop recurrence and die of the disease.[3]

Adjuvant therapies, primarily involving chemotherapy and radiotherapy, have improved treatment and survival in patients with advanced disease[2,4,5] but 5-year survival remains at approximately 50% both for colonic and rectal tumours.[6] This has led to the search for new therapeutic strategies to act as complementary treatments.

Immunotherapy offers one such strategy. It has progressed with recent advances in immunology and molecular biology, the demonstration that colorectal cancer has immunogenic properties[7,8,9,10] and evidence that host immune responses can influence survival.[11,12,13,14] It holds the potential advantage over radiation and chemotherapies in that it selectively targets cancer cells.[15] However, in order to evoke a successful immune response immunotherapies must overcome the mechanisms of immune escape and tumour-induced immune suppression.[16]

There have been promising results from prospective, randomized-controlled clinical trials using active specific immunotherapy (ASI) with autologous tumour cell BCG vaccines.[17,18,19,20] Effective immunization resulted in improvements in stage II disease-free and overall survival.[17,19] Post-operative adjuvant therapy with the monoclonal antibody Edrecolomab (an antibody which binds to the tumour-associated CO17-1 A antigen) restores the immune responses of patients with resected Dukes' C colorectal tumours[21] and has been linked with improved clinical survival.[22] However, two more recent randomized-control studies have not reproduced this survival benefit.[23,24] There are reports of a response to systemic therapy with high-dose interleukin (IL)-2 and lymphocyte-activated killer (LAK) cells in patients with metastatic colorectal cancer that have failed to respond to standard therapy[25,26,27] and preoperative treatment with IL-2 has been linked with improved long-term survival in advanced cancer cases.[28,29] Vaccine therapies using dendritic cells (DC) pulsed with specific tumour antigen peptides to stimulate tumour-specific immunity are now also being trialled in patients with metastatic disease with early results demonstrating an active immune response.[30,31] However, overall results for immunotherapies are currently mixed and it is believed that a better understanding of how the malignant cells circumvent immune surveillance and induce immune suppression could translate into clinical benefit.

The immune system is capable of mounting immune responses to colorectal cancer. This knowledge derives from: (i) the description of at least 10 tumour-associated antigens (TAA) and more than 35 major histocompatibility complex (MHC) class I antigenic epitopes for colorectal cancer;[32] (ii) the estimated detection of partial or complete losses in class I human leucocyte antigen (HLA) in 73% of colorectal carcinomas[33] and (iii) the evidence that intra-tumour inflammatory infiltration occurs and is correlated with improved survival.[11,12,13,14] Unfortunately, whilst this potential for immune surveillance and activation is present, it clearly is not always effective in preventing and/or controlling tumour growth.

Mechanisms of tumour escape from immune recognition/destruction are likely to be multifactorial[34] involving: (i) genetic and cellular changes to tumour cells, rendering them 'immune' to the host's immune response; (ii) host inability to immunologically respond to the tumour cells as they are perceived as 'self' and (iii) blockage or inhibition of the hosts immune response.[35] This review will focus on the evidence to date explaining how colorectal cancer suppresses the immune system.

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