Mechanisms of Resistance to NK Cell Immunotherapy

Abstract

Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

“…In this context, growing evidence suggests that immune checkpoint blockade (ICB)-based therapies, a major breakthrough in the fight against cancer, may reinvigorate immunosurveillance, hence being a therapeutic option for patients with CLL. Although most attention in ICB therapy has been focused on the role of T cells, there is an increasing interest in blocking inhibitory pathways dampening NK cell-mediated responses [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. NK cells from patients with CLL show decreased expression of activating receptors and augmented expression of inhibitory receptors and checkpoint proteins, leading to NK cell dysfunction [ 10 , 24 , 25 ].…”

Potential mechanism prediction of Cold-Damp Plague Formula against COVID-19 via network pharmacology analysis and molecular docking

“…Additionally, CDPF regulates pathways of diseases caused by external organisms, such as bacteria or worms, including pertussis, leishmaniasis, chagas disease, and toxoplasmosis, etc. Immune and inflammatory pathways, such as antigen processing and presentation, natural killer cell mediated cytotoxicity [ 62 ], Fc epsilon RI signaling pathway, associating with the secretion of cytokines, such as TNF-α, contributing to inflammatory responses [ 63 ], TNF signaling pathway [ 64 ], and MAPK signaling pathway [ 65 ], and inflammatory disease-related pathways, such as IBD, are also involved. Sphingolipid signaling pathway utilizes second messenger functions involved in a variety of cellular signalling pathways; sphingolipids appear to be mediators of inflammation and are novel therapeutic targets in inflammatory disease [ 66 ].…”

Monoclonal Antibodies in Cancer Therapy

“…ADCC is partly dependent on recognition through ICAM-1 and CD18, though this appears to be less important for trastuzumab-mediated ADCC [133]. Cancer cell loss of ligands for the activating NKG2D receptor on NK cells such as MICA and dysregulation of the NKG2A-HLA-E axis can also prevent NK cell initiation of ADCC [134]. A recently reported novel mechanism of resistance to ADCC involves the downregulation of multiple cell surface proteins associated with the immune synapse in response to cetuximab and trastuzumab [135].…”