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.
Highlights
Instituto Universitario de Oncología del Principado de Asturias, IUOPA, 33006 Oviedo, Spain; Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
In this review, we only focus on those mechanisms involved in cancer resistance to the the genetic background of the individual, which modulates the biology of Natural killer (NK) cells; the resistance of NK cell-mediated immune response (Figure 1)
Immunotherapy has been a major breakthrough in cancer
Summary
Immunotherapy has been a recent major breakthrough in cancer treatment. Despite most of the current cancer immunotherapies being focused on T cells, NK cells are being increasingly considered to be a key target of immunotherapy (as recently reviewed in [17,18]) (Table 1). Initial clinical trials involving the administration of IL-15 in monotherapy or in combination with NK cells or chemotherapy in patients with hematological and solid tumors are currently ongoing. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide display both direct anti-neoplastic activity on hematological cancer cells and a modulatory effect on multiple immune cell types, including NK cells [44,45]. Lenalidomide increases the expression of NKG2D and DNAM-1 ligands (MICA and PVR) in multiple myeloma [51] These effects support the combination of IMiDs with cytotoxic mAbs, such as rituximab, as a potential therapeutic strategy to be harnessed. A number of anti-neoplastic molecules that possibly influence NK cell activation or NK–tumor cell interactions have been proposed in these latter years, so elucidating the possible synergistic effects of anti-neoplastic drugs and NK cells currently represents an interesting field of investigation [52]
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