Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

Abstract

Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

“…TMAs operate through various mechanisms, exploiting both the targeted variable fragments Fab -ie, by interfering with transduction signaling cascades regulating cell growth and differentiation -and the constant fraction Fc, able to activate the antibody-dependent cell-mediated cytotoxicity (ADCC) and the complement-dependent cytotoxicity. [9][10][11] However, despite the great benefit and improved success rate shown by antibody therapies in the treatment of lymphomas and solid tumors, the clinical practice has raised numerous limitations, mostly related to safety issues. Risks deriving from several adverse reactions, including infection, autoimmune disease and cardiotoxicity, have been associated to TMAs treatment.…”

A cross-sectional study of C-type lectin receptors (CD94 and CD314) in patients with HIV/AIDS and cancer

“…Vpr cause up-regulation of ligands via activation of DNA damage [17] contributing to the depletion of CD4+ T cells [32]. The connection of these ligands with NKG2D induces phosphorylation of the YINM domains in DAP10, which will in turn cause the recruitment and activation of the p85 subunit of phosphatidylinositol-3-kinase (PI3K) and growth receptorbound factor protein 2 (GRB2) means to trigger NK cytotoxicity [9]. These data reinforce the findings of Ward et al (2007) [31], where the expression of NKG2D ligands were increased in CD4+ T cells from seropositive patients, increasing the sensitivity of these cells to destructive action of NK cells, increasing depletion.…”

“…These interactions suggest that the NKG2D may have an important role in immunosurveillance of NK cells against tumor cells and virus-infected cells [2][3][4][5][6][7][8][9][10]. In addition, currently already known that changes in the distribution of these receptors (CD94 and CD314) in lymphocyte subpopulations are important in the pathogenesis of various diseases, such as infections [11] and cancer [12].…”

“…Human NKG2D recognizes MIC-A and MIC-B, which are transmembrane proteins encoded by genes forming part of the HLA complex. Unlike conventional HLA, MIC-A, MIC-B are minimally expressed on normal tissues but have increased expression in cells subjected to stress and tumor cells [9].…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Additionally, they produce several immunostimulating cytokines, most notably TNFα and IFNγ, which in turn activate macrophages and dendritic cells, initiating an antigen-based adaptive immune response. 198 Increased NK infiltration is associated with better prognosis in several types of cancer 208 . In contrast, increased macrophage infiltration correlates with both positive and negative patient outcomes, depending on the type of cancer and the dominant macrophage subset 209,210 .…”