NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis

Abstract

Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8⁺ T cells and natural killer (NK) cells, represents a relevant prognostic factor in CRC and is associated with a better overall survival. Together with NK cells, other innate lymphocytes, namely, innate lymphoid cells (ILCs), have been found both in biopsies of CRC patients and in murine models of intestinal cancer, playing both pro- and anti-tumor activities. In particular, several type 1 innate lymphoid cells (ILC1) with cytotoxic functions have been recently described, and evidence in mice shows a role for both NK cells and ILC1 in controlling CRC metastasis. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions. We also comment on both the described and the potential roles these innate lymphocytes can play during the progression of intestinal cancer leading to metastasis. Finally, we discuss recent advances in the molecular mechanisms underlying the functional regulation of cytotoxic innate lymphocytes in CRC.

Keywords: colorectal cancer; inflammation; innate lymphoid cells; natural killer cells.

Figure 1

Role of NK cells and ILC1 in CRC progression and metastasis. (A) Both NK cells and ILC1 infiltrate CRC at an early stage to block tumor growth. However, tumor-infiltrating NK cells and ILC1 acquire a different phenotype and decrease over time together with their functional abilities. (B) CRC liver metastasization occurs along with the reduction of NK cells in humans and significant alterations of phenotypic and functional properties of NK cells in mice. Arrow indicates a decrease or increase.