Targeting Natural Killer Cells for Tumor Immunotherapy

Abstract

Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous-or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.

Prognostic Significance of Tumor-Infiltrating Natural Killer Cells in Solid Tumors: A Systematic Review and Meta-Analysis

“…On the basis of TNM staging system, a more accurate prognosis prediction system according to the level of these markers could be built in the future, to direct the selection of therapeutic regimens. Further studies are highly encouraged to explore the regulatory mechanisms of the tumor-infiltrating processes of NK cells and the enhancement methods of the anti-tumor effects of TINKs ( 99 ). In addition, targeting the function state of NK cells might be a promising treatment strategy for solid tumors, such as IL-15-mediated CD56 activation ( 100 ).…”

Lipid Metabolism and Cancer Immunotherapy: Immunosuppressive Myeloid Cells at the Crossroad

“…The most relevant types of ACT are tumor-infiltrating lymphocytes (TILs), T cells engineered for T cell receptor (TCR T) and chimeric antigen receptor T cells (CAR T) [ 80 ]. Additionally, genetic modification of NK cells is now providing promising perspectives for cancer treatment [ 81 ]. In the CAR T cell approach, peripheral blood T cells are genetically engineered to overexpress a chimeric TCR that recognizes a tumor-specific antigen in an MHC-independent manner, bypassing antigen presentation by APCs and, simultaneously, supplying the interaction with the co-stimulatory signal (e.g., CD28, CD3ζ) [ 82 ].…”

Natural Killer Cells in Immunotherapy: Are We Nearly There?

“…For example, pharmacological inhibition of Vps34, a kinase involved in autophagy, causes the microenvironment of melanoma and colorectal cancer tumors to become more pro-inflammatory, leading to enhanced recruitment of NK cells and other immune cells, and ultimately more effective anti-PD-1/PD-L1 therapy [143]. An IL-15 superagonist, named N-803 (formerly ALT-803), which has seen widespread success as an immunotherapeutic option for multiple cancers [144,145], is being tested in a phase II clinical trial (NCT03853317) in combination with adoptive CAR-NK cells targeting PD-L1 after promising results in pre-clinical studies [47]. Interestingly, a novel molecule comprising N-803 and anti-PD-L1 domains has shown promise for different carcinoma models [144].…”