Colorectal cancer and immunity: what we know and perspectives

Abstract

Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8⁺ and CD45⁺ lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.

Keywords: Colorectal cancer; Immunity; Immunoregulation; Immunotherapy; Vaccination.

Figure 1

Major mechanisms of tumor immune escape. Tumor cells can induce immunosuppression by different pathways: (1) tumor cells can secrete immunosuppressive cytokines as vascular endothelial growth factor (VEGF), interleukin-10 (IL-10) or transforming growth factor-β (TGFβ). These molecules contribute to blockade of maturation of dendritic cells (DC) and then induce regulatory T cells (Treg) rather than lymphocytes T (LT) CD4⁺ or CD8⁺ cells. VEGF could promote directly induction and proliferation of Treg; (2) Tumor cells down-regulate expression of CMH-1; (3) Tumor cell express inhibitory molecules as PDL1 or CD80, and induce exhaustion of LT; and (4) Tumor cells can evade apoptosis by inducing anti-apoptotic molecules such as C-FLIP, or by down-regulating the expression of death receptors such as FAS.

Figure 2

Main current immunotherapy strategies. A: The goal of vaccination is induction of a specific immunization against tumor antigens. The agent used for immunization can be either a single antigen, administered systemically or directly vectorized path, or a combination of antigens obtained from irradiated tumor cells. Finally, the antigen can be loaded ex vivo in autologous dendritic cells; B: Adoptive cell therapy is based on the ex vivo expansion of immune cells of the host in the presence of tumor cells, allowing the expansion of specific clones. This is mainly T cells but could also involve natural killer cells or a combination of immune cells; C: The non-specific stimulation of the immune system can be obtained by the administration of pro-inflammatory cytokines such as granulocyte-macrophage colony-stimulating factor, or by blocking inhibitory pathways. Ipilimumab is a monoclonal antibody blocking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).