Natural Killer Cell Response to Chemotherapy-Stressed Cancer Cells: Role in Tumor Immunosurveillance

Abstract

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy). However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity.

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

“…The idea of making tumor cells more prone to NK cell killing is not new, but the finding that senescent cells are preferentially recognized and cleared by NK cells extends the field of application. NK cell‐based anticancer therapies are promising and NK cell immunotherapy should be considered as part of a prosenescence therapy. A combined treatment could be conceived in which tumor cells are forced to senescence and then removed by in vivo boosted NK cells or in vitro activated adoptively transferred NK cells.…”

“…114 The idea of making tumor cells more prone to NK cell killing is not new, but the finding that senescent cells are preferentially recognized and cleared by NK cells extends the field of application. NK cell-based anticancer therapies are promising 115,116…”

Does neoadjuvant chemotherapy cancel out the negative survival impact induced by surgical complications after gastrectomy?

“…Chemotherapy is known to be a potential immunomodulatory agent, and No subgroup showed clear superiority in the NIC group versus the IC group. No interactions showed statistical significance among the subgroups many chemotherapy-mediated stress pathways modulate the expression of NK cell-activating and inhibitory ligands, rendering tumor cells more immunogenic [26]. These mechanisms might be involved in the prophylactic effects of NAC.…”

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…Chemotherapeutic agents upregulate stress-related proteins in tumor (as well as other) cells, including ligands for NK cells (Zingoni et al, 2017). For example, low-dose chemotherapeutic agents, including oxaliplatin, are capable of upregulating ligands for the activating receptors NKG2D and DNAX accessory molecule-1 (DNAM-1; CD226) and TRAIL in multiple tumor lines leading to enhanced susceptibility to NK cell cytotoxicity (Soriani et al, 2009;Siew et al, 2015).…”