Immunology and immunotherapy of colorectal cancer

Abstract

There are at least three immune hallmarks of cancer: (1) it is able to thrive in a chronically inflamed microenvironment, (2) it can evade immune recognition, and (3) it is able to suppress immune reactivity. For colorectal cancer (CRC), there are many evidences connecting tumori genesis and inflammation, such as the decreased incidence of tumors in individuals under nonsteroidal anti-inflammatory drug treatment. The increased incidence of tumors in overweight patients points out to adipose tissue inflammation, energy metabolism, genetic instability, and their relationship with commensal bacteria, altogether affecting inflammation both locally and systemically. Tumor cells have developed several immunosuppressive mechanisms to avoid their elimination, such as the impairment of specialized antigen presentation cells or the recruitment of regulatory cell populations such as regulatory T lymphocytes (Treg). The present knowledge of the tumor microenvironment at the molecular and cellular levels is being used to reverse the situation in favor of the patient through targeted therapies such as the use of tyrosine kinase inhibitors or procedures that specifically activate an immune reaction directed against tumor cells, such as T-cell adoptive transfer, in some cases of genetically engineered cells. Among the multiple procedures available to stimulate the immune system, monoclonal antibodies (mAbs) can be used either to activate cytotoxic cells or to inhibit tumor cell activities by binding to certain plasma membrane receptors or their ligands. Three mAbs have been approved by the European Medicines Agency (EMEA) for the treatment of CRC, two of them blocking the epidermal growth factor receptor (EGFR) and the other one blocking the binding of vascular endothelial growth factor (VEGF) to its receptors. Finally, another way to specifically activate an antitumoral response is related to the innate immunity and the development of therapeutic vaccines. This approach has evolved dramatically in the past years mainly due to the discovery of five families of pattern recognition receptors, including the Toll-like receptors. The first therapeutic vaccine approved by the Federal Drug Administration (FDA) in 2010 was against metastatic prostate cancer. Several experimental vaccines for colorectal cancer are still in phase I or II clinical trials and their results will undoubtedly pave the road to the development of new drugs and treatments for this cancer.