The changing role of natural killer cells in cancer metastasis

Abstract

Natural killer (NK) cells are innate immune cells that are critical to the body's antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.

Figure 1. The varied roles of NK cells during metastasis.

NK cell activity varies in different organs and at different stages of metastasis. Contributing to the different functions of NK cells are the changes within the cancer cell that occur at each stage. Initially NK cells control metastasis by targeting highly invasive metastatic cells that express K14 and lack MHC class I molecules (14). However, as cancer cells change their shape, features, and molecular composition during the process of metastasis, they can alter the function of NK cells as a mode of immune escape. As polyclonal clusters of metastatic cancer cells disseminate and circulate, they display increased epithelial behavior (55) and recruit neutrophils that shield them from NK cell attack (69). During colonization of a distal organ, increases in TGF-β (61) and PGE₂ (65) in the tumor microenvironment (TME) inactivate NK cells. Dormant cancer cells in colonized tissue express DKKs to suppress NK cell activity (37, 40). Finally, NK cells undergo reprogramming to express inhibitory rather than activating receptors as metastatic cancer cells proliferate into macrometastases, and the reprogrammed NK cells can promote tumor growth (14).

Figure 2. Signaling interactions between NK cells and cancer cells in the tumor microenvironment.

Natural killer cells within the tumor microenvironment are governed by a series of signals from cancer cells and from other immune cells that are present. During metastasis, exposure to cancer cells can alter these signals to activate or inactivate the NK cells or alter them toward a tumor-promoting phenotype.