The immunology of colorectal cancer

Abstract

Despite the fact that the vast majority of differentiated colorectal cancers express tumour-associated antigens (TAA's) such as Carcinoembryonic antigen (CEA) and Ep-CAM, the immune response particularly in advanced disease is often attenuated. This may result from clonal immunocyte energy to oncofetal antigens normally expressed during cell development, immune complex disease where the TAA is repeatedly shed into the circulation and tumour-induced impairments in T cell receptor recognition and stimulation. Commonly used monoclonal anti-TAA antibody therapy is also hampered by human anti-xenogeneic antibody production and by the physical distribution of the antibody into the center of tumour deposits where blood flow is limited and where tumour neovasculature is hyperpermeable. Moreover, animal models of colorectal cancer should be assessed carefully since CEA is not normally expressed, requiring the transduction of CEA cDNA into tumour xenografts or the creation of transgenic species where the mechanisms of tumour rejection are still governed by non-human antigenic histoincompatibility. All of this has resulted in the generation of novel immune constructs designed to enhance the inherent immunogenicity of colorectal cancer, using antigenic viral genomes or cytokine transduction methodology as well as the ex vivo stimulation of dendritic antigen-presenting cells or autologous tumour-infiltrating lymphocytes. Even these powerful strategies may be foiled by intratumoural mechanisms which result in excessive apoptosis of infused cells even when they have been shown in vitro to be immunocompetent and tumour-specific. This review discusses these immune approaches in colorectal cancer and their inherent limitations.

Introduction

Colorectal cancer is one representative model for derangement in immune responses. It is also a prime candidate for specific immunotherapy designed to target the prominent tumour-associated antigens (TAA) expressed on the surface of tumour cells or to potentiate cytotoxic immunocytes within the tumour microenvironment. This field of therapy is emerging in concert with the postulated multi-step model of colorectal tumorigenesis, in which there is the sequential accumulation of a series of genetic mutations in the progression from benign adenoma to malignant invasive carcinoma [1]. Much has been made of the initial results of monoclonal anti-TAA immunotherapy. When utilized as an adjuvant in high-risk Dukes’ C colon cancer, the monoclonal antibody 17-1A (ant-EpCAM) provided a sustainable survival advantage [2] and a reduction in locoregional recurrence rates [3], although this effect has not been reproduced in recent studies of second-generation anti-TAA therapy with purified anti-idiotypic antibodies [4], [5].

These approaches have later been varied, with initially poor results using non-specific immune stimulants [6], [7] and progress toward anti-TAA therapies. The latter include passive and active specific immunotherapies employing attenuated tumour cell vaccines, tumour cell lysates, cancer-specific peptides, carbohydrate antigens, genetic constructs encoding for colorectal tumour antigens and in vitro-stimulated dendritic cell therapies capable of recognizing tumour peptides on the surface of colorectal cancer cells residing in relatively privileged environments [8], [9], [10], [11], [12], [13], [14]. This review concerns basic immunology as it pertains to colorectal cancer. It will consider the nature of colorectal TAAs that may function as immunological targets and the strategies for immunotherapy. It will also describe some immunological barriers to elimination by the potentially immunocompetent cytotoxic lymphocytes that infiltrate colorectal cancer deposits.