Abstract
Natural killer (NK) cells are major contributors to immunosurveillance and control of tumor development by inducing apoptosis of malignant cells. Among the main mechanisms involved in NK cell-mediated cytotoxicity, the death receptor pathway and the release of granules containing perforin/granzymes stand out due to their efficacy in eliminating tumor cells. However, accumulated evidence suggest a profound immune suppression in the context of tumor progression affecting effector cells, such as NK cells, leading to decreased cytotoxicity. This diminished capability, together with the development of resistance to apoptosis by cancer cells, favor the loss of immunogenicity and promote immunosuppression, thus partially inducing NK cell-mediated killing resistance. Altered expression patterns of pro- and anti-apoptotic proteins along with genetic background comprise the main mechanisms of resistance to NK cell-related apoptosis. Herein, we summarize the main effector cytotoxic mechanisms against tumor cells, as well as the major resistance strategies acquired by tumor cells that hamper the extrinsic and intrinsic apoptotic pathways related to NK cell-mediated killing.
Highlights
Natural killer (NK) cells are large granular innate lymphoid cells
Cancer-associated fibroblasts (CAFs) display a suppressive activity that partially relies on PRF1 downmodulation in NK cells [110,111,112]. This mechanism of NK cell evasion affects PRF1 expression; several studies have reported lower levels of GZMB, as well as, CD107a in tumor-infiltrating NK cells, an altered phenotype that translates into an attenuated antitumor immune response [107,108,115,124,235]. Apart from this extended evasion strategy, an early study involving acute myeloid leukemia (AML) samples revealed that the intrinsic apoptosis resistance associated with this type of cancer relies on an impaired binding of PRF1 to the surface of the tumor cells [113]
The antitumor function of the immune system strongly relies in the induction of apoptotic malignant cell death by certain cytotoxic lymphocytes
Summary
Natural killer (NK) cells are large granular innate lymphoid cells. This immune subset is in charge of recognizing and eliminating viral-infected and tumor-transformed cells in an antigen-independent manner, playing a key role in the immune control of tumor development and metastasis [1,2,3]. Activation of programmed cell death signaling appears to be a central player in preventing tumor progression, since resistance to apoptosis has been defined as a hallmark of cancer [15] In this context, two main mechanisms are responsible for NK cell-mediated cytotoxicity resistance: 1) tumor cells take advantage of co-inhibitory signaling to avoid NK cell-mediated responses, leading this immune subset to an anergic or irresponsiveness state, and 2) tumor cells avoid NK cell effector activity after target cell recognition (i.e., inefficient perforin (PRF1) binding). We summarize the major mechanisms affecting NK cell-mediated apoptosis and resistance in cancer
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