Involvement of natural killer cells in the pathogenesis of lymphomas: Therapeutic implications

Natural killer cells play a pivotal role in the control of various infectious diseases and malignancies. Their functional activities are impaired in many cancers and, both directly and indirectly, participate in the progression of cancer and escape from immune surveillance. Their role in the regulation of anticancer adaptive immunity is consequently compromised. This is the case also in lymphoid malignancies where they are modified phenotypically and functionally lose their antitumor cytotoxic activities and cytokine secretion. Based on these important roles of NK cells in lymphomas, several new strategies have been devised to either reactivate them in vitro and/or adaptively administer ex vivo generated activated NK cells with anticancer activities. These include, for example, the use of agonist antibodies directed against NK activating receptors or the use of antagonists directed against the NK inhibitory receptors or checkpoint inhibitors. In addition, the adaptation of NK cell lines that have been modified, such as CAR-NK cells, as donor cells are compatible with the allogeneic hosts and are not rejected, while exerting significant antitumor activities when used alone or in combination with other therapeutics. Such novel therapeutic approaches by NK cells in the treatment of lymphomas are currently in preclinical and clinical studies for their validation and approval.