Plasticity of NK cells in Cancer

Abstract

Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or via orchestration of the broader immune response. NK cells exist across a wide range of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.

Gross Total Resection Promotes Subsequent Recovery and Further Enhancement of Impaired Natural Killer Cell Activity in Glioblastoma Patients

“…Given the pleiotropic roles of different NK subsets on tumor immunity [ 33 ], we next examined whether surgical resection of glioblastoma affects the distribution of NK cell subsets as well as T cell subset. As shown in Figure 2 A, the CD56 bright CD16 − NK subset was significantly decreased on POD3 (median: 1.1% vs. 0.5%, p = 0.022, compared with baseline).…”

Promising immunotherapeutic targets in lung cancer based on single-cell RNA sequencing

“…Compared with the early stage of lung cancer, CD16 + NK cells were decreased, and the CD16 − NK cluster was highly enriched in advanced NSCLC (30). In addition, a population of tissue-resident NK (trNK) referred to as intraepithelial ILC1 (ieILC1), has been defined as CD56 + CD16 -CD127 -tBET + EOMES + cells and can be recognized by the expression of CXCR6 and resident markers, including CD49a, CD103, and CD69 (64,65). IeILC1 exerts potent anti-tumor effects by producing granzyme B and perforin.…”

“…However, there is a need for further research to explore the connection between PD-1 and TIM-3 and their role in promoting NK exhaustion in lung cancer. To some extent, the phenotype of exhausted NK cells overlaps with that of trNK cells, indicating that trNK may be further transformed into the exhaustion phenotype (65). Although the heterogeneity and functions of NK cells have been partially revealed, the dynamics of NK cell dysfunction in the TME still require further investigation.…”

Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox

“…However, NK cells also possess plasticity, which can be polarized to a pro-tumor type in response to the TME signals, as well as promote tumor angiogenesis and metastasis [ 45 , 46 ].…”