The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies

Abstract

Natural killer (NK) cells belong to the innate immune system and contribute to protecting the host through killing of infected, foreign, stressed or transformed cells. Additionally, via cellular cross-talk, NK cells orchestrate antitumor immune responses. Hence, significant efforts have been undertaken to exploit the therapeutic properties of NK cells in cancer. Current strategies in preclinical and clinical development include adoptive transfer therapies, direct stimulation, recruitment of NK cells into the tumor microenvironment (TME), blockade of inhibitory receptors that limit NK cell functions, and therapeutic modulation of the TME to enhance antitumor NK cell function. In this Review, we introduce the NK cell-cancer cycle to highlight recent advances in NK cell biology and to discuss the progress and problems of NK cell-based cancer immunotherapies.

Figure 1.

Human and Mouse NK cells. Simplified human and mouse NK cells can be subdivided into three main subsets based on the expression of CD56 and CD16 in human and CD11b and CD27 in mice. Depicted are important molecules required for NK cell recruitment, activation and effector function in the TME.

Figure 2.

The NK cell-Cancer Cycle. To effectively eliminate cancer cells, the body needs to initiate a self-propagating anti-tumor immune response. The NK cell-cancer cycle consists of 4 steps important to initiate and maximize the efficacy of this innate response. 1. NK cells need to be recruited into the TME; 2. NK cells recognize cancer cells and undergo full activation; 3. NK cells kill cancer cells locally and systemically; 4. NK cell orchestrate innate and adaptive immunity e.g. by alerting dendritic cells. Finally, due to elimination of cancer cells locally in the TME or at distant sites antigens, chemokines and danger associated molecular patterns are liberated further fueling innate adaptive responses and allowing the cycle to begin again.

Figure 3.

Positive and negative molecules influencing the NK cell-Cancer Cycle. Each step in the NK cell-Cancer Cycle is affected by a variety of stimulatory or inhibitory signals integrated by NK cells. Positive molecules are depicted in green and promote NK cell activity, while molecules negatively affecting NK cell activity are shown in red. These negative signals are required to prevent overshooting immune responses leading to exacerbated tissue damage. However, in the TME these pathways are hijacked by the cancer cells to escape NK cell mediated immunity and to scotch the initiation of adaptive immunity.

Figure 4.

Therapies affecting individual steps of the NK cell-Cancer cycle.