Natural Killer Cells for Cancer Immunotherapy: Opportunities and Challenges

Abstract

Natural killer (NK) cells are advantaged immune cells and play a pivotal role in both innate and adaptive immune responses. To date, autogenous and allogenic NK cells have been generated from a variety of origins, including perinatal blood (e.g., umbilical cord blood and placental blood), peripheral blood, and even stem cells (hematopoietic stem cells and pluripotent stem cells). NK cells function mainly via antibody-dependent cell-mediated cytotoxicity (ADCC), direct cytolytic effect, and paracrine effects (e.g., IFN-γ, GM-CSF, granzyme, and perforin). Distinguishing from the adaptive immunizing cells (e.g., T and B lymphocytes), NK cells, and chimeric antigen receptor-transduced NK (CAR-NK), cell-based cytotherapy is adequate to fulfill the biofunction of eliminating pathogenic infection, combating hematological malignancies and metastatic solid tumors, and delaying aging. In this chapter, we mainly focus on the state-of-the-art renewal of NK cell-based cytotherapy for cancer immunosurveillance and immunotherapy from the view of high-efficient in vitro preparation (e.g., candidate cell sources and ex vivo cultivation) and preclinical and clinical investigation. Furthermore, we also figure out the promising prospects and the concomitant challenges of NK cell-based remedies for cancer management in future, which will collectively benefit the development of NK cell-based cancer immunotherapy in future.

The application of autologous cancer immunotherapies in the age of memory-NK cells

“…Memory-like (ML) NK cells can ignore some inhibitory receptors, such as KIR, and exhibit higher expression of the activating receptors, such as NKG2D, NKp46, and DNAM-1, suggesting their potential effectiveness in recognizing additional tumor types ( 26 ). ML NK cells show various features, such as longer persistence, higher proliferation, and extended effector function ( 58 ), that provide superior host protection, higher expansion, and higher IFN-γ production than conventional NK cells ( 59 ). In humans, the increased output of IFN-γ by ML NKs was correlated to the expression of NKp46, CD94, NKG2A, and CD69 receptors, as well as the lack of CD57 and KIR receptors ( 56 ).…”

“…Since NK possess several activation receptors, this concept was ideal to be used for the design of CAR-NK cells ( 130 ). These modifications intend to overcome the limitations of non-modified NK cells when facing tumor cells with genetic or epigenetic variations that bypass the NK immunological surveillance ( 51 , 58 ). CAR-NK cells can be produced from multiple sources (such as peripheral blood, cord blood, iPSCs, and NK-92 cell line), adopting the basic methods borrowed from CAR-T cell generation ( 131 ).…”

Nanomaterials as Novel Biomarkers for Cancer Nanotheranostics: State of the Art

“…Cancers with high heterogeneity and uncontrolled cell division are notoriously hard to conquer and have emerged as one of the leading causes of death worldwide with a prevalence of over 10 million mortalities annually [1,2]. Over the years, a certain number of investigations have been accomplished to figure out the fundamental pathogenesis and the concomitant treatment regimens including surgery, oncolytic virotherapy, radiotherapy, chemotherapy, photothermal therapy, RNA vaccine, peptide-based neoantigen vaccine, hormone therapy, and immunotherapy [3][4][5][6]. Generally, surgery (e.g., robotic surgery, laparoscopic rectal surgery) has been considered the best option for localized cancers without transfer and diffusion, which usually works in combination with chemoradiotherapy for the eradication of residual cancerous cells [7,8].…”

“…Chemoradiotherapy has become a notable and synergistic anticancer treatment for a variety of locally advanced solid tumors through a rationale of two concepts (chemotherapy, radiotherapy) of in-field cooperation and spatial cooperation but inevitably increases microbiota resistance and damage to normal tissues [9][10][11]. Current progresses have also highlighted the potential of anticancer immunotherapy including immune cells and checkpoint inhibitors for the significant clinical benefit [3,4,9,[12][13][14]. Meanwhile, despite new insights into RNA vaccine-derived immunity in melanoma treatment, those cancer vaccine trials in the late-stage patients with various treatment-refractory tumors have not been successful [6,[15][16][17].…”

“…Meanwhile, despite new insights into RNA vaccine-derived immunity in melanoma treatment, those cancer vaccine trials in the late-stage patients with various treatment-refractory tumors have not been successful [6,[15][16][17]. Therefore, in overall consideration of the shortcomings (e.g., off-target effects, severe toxicity, drug delivery barriers, and graft-versus-host disease), the aforementioned treatment regimens fell short of expectation in cancer administration [1,3,12,[18][19][20].…”