Cord Blood-Derived Natural Killer Cell Exploitation in Immunotherapy Protocols: More Than a Promise?

Abstract

In the last 20 years, Natural Killer (NK) cell-based immunotherapy has become a promising approach to target various types of cancer. Indeed, NK cells play a pivotal role in the first-line defense against tumors through major histocompatibility complex-independent immunosurveillance. Their role in the control of leukemia relapse has been clearly established and, moreover, the presence of NK cells in the tumor microenvironment (TME) generally correlates with good prognosis. However, it has also been observed that, often, NK cells poorly infiltrate the tumor tissue, and, in TME, their functions may be compromised by immunosuppressive factors that contribute to the failure of anti-cancer immune response. Currently, studies are focused on the design of effective strategies to expand NK cells and enhance their cytotoxic activity, exploiting different cell sources, such as peripheral blood (PB), umbilical cord blood (UCB) and NK cell lines. Among them, UCB represents an important source of mature NK cells and CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs), as precursors of NK cells. In this review, we summarize the UCB-derived NK cell activity in the tumor context, review the different in-vitro models to expand NK cells from UCB, and discuss the importance of their exploitation in anti-tumor immunotherapy protocols.

Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

“…Most importantly, cord blood NK cells have better homing ability and are less immunogenic due to the higher chemokine receptor expression on cord blood-derived NK cells and lesser T cells isolated from cord blood ( 33 ). Nevertheless, NK cells from cord blood are immature and express lower expression of granzyme B and activating receptors such as CD16 and DNAM-1 ( 34 ). Furthermore, the higher expression of inhibitory receptors on cord blood NK cells hinders their function to kill cancer cells effectively ( 34 ).…”

Efficacy of nature killer cell combination chemotherapy for post-radical gastric cancer metastases: Case report

“…Activated and amplified NK cells can be obtained from different sources, including NK cell lines, primary NK cells, umbilical cord blood (UCB) NK cells, and induced pluripotent stem cell-derived NK cells. 7 NK cells have multiple pathways for killing tumors. One of the pathways for NK cells to kill tumor cells is that NK cells can release perforins and granzymes, which induce apoptosis in target cells.…”

New cell sources for CAR-based immunotherapy

“…Compared to PB NK cells, UCB NK cells have a better proliferation capacity; however, they are naive in phenotype and function with low cytolytic activity and limited ADCC. Nonetheless, there are several ongoing clinical trials with UCB-derived CAR-NK cells in hematological malignancies [ 184 , 185 ] (Table 2 ). Overall, the number of CAR-NK clinical trials has rapidly increased in recent years, with multiple targets being explored in hematological (CD5, CD7, CD19, CD22, CD33, CLL1, BCMA, CD70, CD123) and solid (NKG2DL, HER2, MUC1, PSMA, Mesothelin, ROBO1, DLL3, CLDN6, 5T4, PD-L1) malignancies (Table 2 ).…”