Immunosenescence: limitations of natural killer cell-based cancer immunotherapy

Abstract

Cancer is primarily considered a disease of old age. Immunosenescence refers to the age-associated changes in the immune system, and its contribution to the increased risk of cancer in old individuals has been discussed for many years. Natural killer (NK) cells are cytotoxic innate immune cells specialized in defence against tumour and virus-infected cells. NK cell cytotoxicity is the result of a fine balance between activating and inhibitory receptors. Several activating receptors have been identified that recognize different ligands frequently found over-expressed on tumour cells or virus-infected cells. The most important NK cell inhibitory receptors interact with major histocompatibility complex class I molecules expressed on almost all nucleated cells preventing NK cell-mediated lysis of healthy cells. NK cell immunosenescence is characterized by a redistribution of NK cell subsets, a diminished expression of several activating receptors and lower per-cell cytotoxicity. Altered expression of activating receptors has also been described in young and elderly cancer patients probably due to chronic exposure to ligands on tumour cells. Thus, the effect of both age and cancer may act synergistically to diminish NK cell-mediated tumour immunosurveillance. Different strategies harnessing the power of NK cells to target tumour cells have been designed including adoptive therapy with autologous or allogeneic expanded NK cells. In addition, checkpoint blockade of inhibitory receptors and the use of agonist antibodies to stimulate activating receptors are emerging areas of research. In this context, the effect of immunosenescence should be considered to improve the efficiency of cancer immunotherapy.

Senescent cells: Living or dying is a matter of NK cells

“…It would be interesting to verify whether NK cell number negatively correlates with senescent cell accumulation in aging tissues. Cells of the immune system, including NK cells, display a senescent phenotype with increasing age, a process called immunosenescence . The idea of ameliorate aged tissue functionality by killing senescent cells is supported by different studies …”

“…Cells of the immune system, including NK cells, display a senescent phenotype with increasing age, a process called immunosenescence. [101][102][103] The idea of ameliorate aged tissue functionality by killing senescent cells is supported by different studies. [104][105][106] Anticancer prosenescence therapies are currently under investigation, 27,107,108 and recently approved drugs, such as CDK4/6 selective inhibitors, have been shown to induce tumor senescence.…”

The Transcription Factor ZNF683/HOBIT Regulates Human NK-Cell Development

“…The obtained results show clear benefits of NK cell-based therapies, in comparison to T lymphocyte-based, including a good tolerance of allogeneic NK cells by the patients and the lack of a graft-versus-host disease (1, 25). Different strategies are exploited to obtain a sufficient number of NK cells for infusion therapies, including cytokine- and/or feeder cell-mediated expansion of peripheral blood NK cells as well as ex vivo differentiation from cord or peripheral blood-derived HSC (26, 27). In this regard, we have previously analyzed a feeder cell-free ex vivo system to generate large-scale therapeutic NK cells from cord blood stem cells that faithfully reproduces different steps of human NK-cell differentiation (28).…”

Changes of peripheral lymphocyte subsets and cytokine environment during aging and deteriorating gastrointestinal tract health status

“…The immune therapies in the last decades are mostly based on the clinical successes of immune checkpoint blockade and adoptive T cell transfer, which motivates our own immune system to fight against the cancer cells [ 44 , 45 ]. Although NK cells play roles in the host defense of tumor, the immune therapy based on NK cells is limited by the requirement of a large number of functional NK cells [ 46 ]. Based our findings, a new strategy which restore the expression of CD16 on NK cells should be taken into consideration, which might guarantee the function of autologous NK cells.…”