Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies

Abstract

Natural killer (NK) cells belong to the family of innate immune cells with the capacity to recognize and kill tumor cells. Different phenotypes and functional properties of NK cells have been described in tumor patients, which could be shaped by the tumor microenvironment. The discovery of HLA class I-specific inhibitory receptors controlling NK cell activity paved the way to the fundamental concept of modulating immune responses that are regulated by an array of inhibitory receptors, and emphasized the importance to explore the potential of NK cells in cancer therapy. Although a whole range of NK cell-based approaches are currently being developed, there are still major challenges that need to be overcome for improved efficacy of these therapies. These include escape of tumor cells from NK cell recognition due to their expression of inhibitory molecules, immune suppressive signals of NK cells, reduced NK cell infiltration of tumors, an immune suppressive micromilieu and limited in vivo persistence of NK cells. Therefore, this review provides an overview about the NK cell biology, alterations of NK cell activities, changes in tumor cells and the tumor microenvironment contributing to immune escape or immune surveillance by NK cells and their underlying molecular mechanisms as well as the current status and novel aspects of NK cell-based therapeutic strategies including their genetic engineering and their combination with conventional treatment options to overcome tumor-mediated evasion strategies and improve therapy efficacy.

Enhanced CT-based radiomics model to predict natural killer cell infiltration and clinical prognosis in non-small cell lung cancer

“…In immunotherapeutic strategies, NK cells also play an important role. Many tumors, including NSCLC, exploit inhibitory pathways to escape NK cell-mediated killing (33,34). New therapies aim to block these inhibitory signals (like KIRs, NKG2A) to enhance NK cell activity (35,36).…”

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

“…NK cells are a signifcant component of the nonspecifc immune response that exert antitumor efects by both direct cytolytic activity and the secretion of immunostimulatory cytokines [13][14][15][16]. Studies have confrmed that the occurrence of many tumors is related to the loss of the recognition function of NK cells, which is also one of the main mechanisms of tumor immune evasion [17][18][19][20]. Te release of lytic granules containing granzymes and perforin mediates the cytolytic activity of NK cells via binding death receptors on tumor cells, and this can be demonstrated by the expression of CD107a on the surface of NK cells.…”

Viral escape from NK‐cell‐mediated immunosurveillance: A lesson for cancer immunotherapy?

“…The interplay between viral escape strategies and compensatory mechanisms that enable NK cells to protect their host despite such evasion attempts might thus serve as a valuable lesson for anticancer NK-cell responses. Leveraging knowledge obtained from antiviral immune responses may allow for rationally designing NK-cell-based cancer immunotherapies, further boosting their considerable clinical promise despite substantial tumor immune evasion [106][107][108][109][110][111].…”