Colon cancer and the immune system: the role of tumor invading T cells

Abstract

Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.

Figure 1

A proposed model for the host immune reaction to cancer cells. At the initiation of the immune reaction lymphocytes and other cells participating in innate immunity (e.g. APCs, NK, NKT cells) recognize transformed tumor cells and produce IFN-γ. This starts a cascade of reactions with production of chemokines (for instance angiogenic or angiostatic chemokines like MIG, IP10 and I-TAC), IFN-γ (antiproliferative mediator for the developing tumor) and direct cytotoxicity of NK cells and macrophages on tumor cells. This cascade may result in partial tumor cell death and tumor cell debris is ingested by dendritic cells, which move to draining lymph nodes and activate CD4+ and CD8+ T cells. Activated and tumor specific T cells move to the tumor along a chemokine gradient and destroy tumor cells expressing a distinctive tumor antigen.

Figure 2

The role of different T cell subsets in colorectal cancer. Activated CD4+ T cells can release growth factors and thereby lead to tumor progression or activate tumor specific CD8+ T cells. Secretion of TGFβ can induce adaptive Tregs, which may suppress the anti-tumor immune response. Once activated, Tregs can be suppressed by IL-6 derived from CD4+ T cells.