NK Cell Inflammation in the Clinical Outcome of Colorectal Carcinoma

Abstract

The ability of natural killer (NK) cells to provide protection against myeloid leukemia has been demonstrated in clinical settings. However, whether NK cells play a role in the clinical course of solid tumors is debated. The controversy surrounding the role of NK cells is due, at least in part, to the limited extent of NK cell infiltration found in the tumor bed. Inactivation of NK cells may explain the shortage of NK cells in the microenvironment of colorectal cancer (CRC). Upon NK cell/tumor cell interaction, tumor cells may escape NK cells by creating an immunosuppressive microenvironment, which possibly affects T-cells as well. Such an immunosuppressive microenvironment would hamper the functions of NK and T-cell and reduce NK and T-cell interactions. CRC patients with levels of tumor NK cell infiltration suitable for statistical analysis have been identified. The infiltration of the CRC microenvironment by NK cells, in combination with CD8(+) T-lymphocytes, has been shown to enhance the prognosis of CRC patients. Here, we discuss the clinicopathological role of NK cells in CRC, and present clinical data indicating a potential supporting role for NK cells in the anti-CRC effects of CD8(+) T-cells.

Keywords: CD8+ T cells; NK cells; colorectal carcinoma; cooperation; inflammation; survival.

Figure 1

CD16^low NK cells surviving CRC-cell-induced dysfunction boosted the CD8⁺ T-cell-dependent anti-CRC tumor immune response. CD16^high NK cell conjugation with CRC cells led to the elimination of both NK and CRC cells. MMP activation and TNF-α production resulted in a population of CD16^low NK cells that survived cancer-cell-contact and remained functionally active. These cells produced IFN-γ, leading to upregulation of HLA class I antigen(s) on cancer cells. HLA class I upregulation enhanced tumor antigen presentation to CD8⁺ T-cells. Conversely, the cancer cells protected themselves from CD16^low NK-cell-mediated cytotoxicity through the release of soluble MICA/B.

Figure 2

Crosstalk between NK cells and T-cells could shape a proinflammatory immune response. Activated T-cells produced IL-2, and CRC cells produced HMGB1. IL-2 and HMGB1 in combination activated NK cells to produce leptin and IFNγ. The latter induced de novo expression of HLA class II antigens by CRC cells. HLA class II antigens, presumably by interacting with the CD4 antigen, may promote IL-6 production by macrophages. Leptin may then directly stimulate macrophages to produce IL-1β, which then stimulates T-cells to synthesize IL-6.