Mechanisms of Immunosuppression in Colorectal Cancer

Abstract

CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

Keywords: cell surface protein; colorectal cancer; cytokine; immunosuppression; immunotherapy; metabolic alteration; microsatellite stable; phosphatase; transcriptional factor.

Figure 1

A simplified schematic showing how immunosuppressive cells in the TME assist tumor cells escape from immunosurveillance. In the TME, the immunostimulatory cytokines (IL-2, IFN-γ, IL-15, etc.) may enhance or activate immunity against tumor cells. Nevertheless, immunosuppressive cytokines (PD-L1, TGFβ, etc.) secreted by immunosuppressive cells or cancer cells may inhibit proliferation or activation of naïve CD4⁺ T cells and tumor-killing immune cells, including natural killer (NK) cells, CD8⁺ T cells, and NKT cells. Meanwhile these immunosuppressive cytokines (CCR4, CCL20, TGFβ, etc.) secreted by tumor-associated macrophages (TAMs), mast cells, and bone marrow myeloid cells (BMMCs) may assist tumor infiltration of immunosuppressive cells, such natural T regulatory cells (Tregs) and TAMs, and support proliferation or activation of immunosuppressive cells, such as Tregs. Immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and Tregs, may also inhibit the function or activation of NK cells, T cells, and NKT cells independent of cytokines.