Abstract
Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world and is characterized by the accumulation of clonal CD5+/CD19+ B cells in peripheral blood, lymph nodes, spleen and bone marrow [1,2]
This hypothesis is supported by several pieces of in vitro evidence showing that natural killer (NK) cell functions are retained and/or recovered after an appropriate stimulation, leaving hope that NK cells can be ideal candidates for CLL immunotherapy
As several immune checkpoints are expressed on both NK and T cells, it is difficult to establish how much of the clinical benefit of checkpoint blockade is attributed to NK cells, unless CLL cells have lost human leukocyte antigen (HLA)-class I molecules
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world and is characterized by the accumulation of clonal CD5+/CD19+ B cells in peripheral blood, lymph nodes, spleen and bone marrow [1,2]. The development of targeted therapies, such as the inhibitors of B cell receptor (BCR) signaling and of B cell lymphoma 2 (Bcl-2) protein, has changed the treatment landscape of CLL [5] Despite their remarkable antitumor activity, targeted agents have shown some limitations, including the development of drug resistance and the low efficacy in high-risk patients [6,7]. The critical role of NK cells in targeting human tumors emerges from the seminal studies of Velardi’s group on haplo-HSCT against AML [29,30], which have paved the way for intense research on NK cell-based cancer immunotherapy In this context, as endogenous NK cells are defective in both solid tumors [99,100] and hematological malignancies [101,102], several efforts have been made to discover strategies for restoring and/or bolstering NK cell functions or for providing patients with functional NK cells [103]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
