Abstract
Primary human natural killer (NK) cells recognize and subsequently eliminate virus infected cells, tumor cells, or other aberrant cells. However, cancer cells are able to develop tumor immune escape mechanisms to undermine this immune control. To overcome this obstacle, NK cells can be genetically modified to express chimeric antigen receptors (CARs) in order to improve specific recognition of cancer surface markers (e.g., CD19, CD20, and ErbB2). After target recognition, intracellular CAR domain signaling (CD3ζ, CD28, 4-1BB, and 2B4) leads to activation of PI3K or DNAX proteins (DAP10, DAP12) and finally to enhanced cytotoxicity, proliferation, and/or interferon γ release. This mini-review summarizes both the first preclinical trials with CAR-engineered primary human NK cells and the translational implications for “off-the-shelf immunotherapy” in cancer treatment. Signal transduction in NK cells as well as optimization of CAR signaling will be described, becoming more and more a focal point of interest in addition to redirected T cells. Finally, strategies to overcome off-target effects will be discussed in order to improve future clinical trials and to avoid attacking healthy tissues.
Highlights
Natural killer (NK) cells are peripheral blood lymphocytes that mediate immune surveillance in regard to virus infected and malignant cells [1,2,3]
Recognition of aberrant and stressed cells occurs by means of activating cell surface receptors including natural killer group 2 member D (NKG2D) (CD314), NKp30 (CD337), NKp46 (CD335), and NKp44 (CD336) [8], receptor complex CD94/NKG2C [9], or FCγRIII (CD16) for antibodydependent cellular cytotoxicity (ADCC) [10,11,12]
Examples for these receptors are several receptors of the killer cell Ig-like receptors (KIRs) family (CD158), NKG2A that pairs with CD94 to a heterodimer, leukocyte immunoglobulin-like receptor (LILR), natural killer cell receptor protein 1 (CD161), sialic acid-binding immunoglobulin-like lectin-7 (CD328), leukocyte-associated Ig-like receptor 1 (LAIR-1; CD305), killer cell lectin-like receptor G1, carcinoembryonic antigen-related cell adhesion molecule (CD66a), paired immunoglobulin-like receptor α, and CD300a
Summary
Natural killer (NK) cells are peripheral blood lymphocytes that mediate immune surveillance in regard to virus infected and malignant cells [1,2,3]. Recognition of aberrant and stressed cells occurs by means of activating cell surface receptors including natural killer group 2 member D (NKG2D) (CD314), NKp30 (CD337), NKp46 (CD335), and NKp44 (CD336) [8], receptor complex CD94/NKG2C [9], or FCγRIII (CD16) for ADCC [10,11,12]. Tumors can develop tumor immune escape mechanisms to protect themselves from NK cell attack, e.g., by matrix metalloproteinase-dependent proteolytic cleavage of MHC class I polypeptide-related sequence A and B (MICA and MICB) [14] These soluble immunosuppressive molecules decrease NK cell cytotoxicity by reduction of NKG2D expression that leads to attenuated recognition of target cells. The present review will discuss the use of primary NK cells isolated from peripheral blood for CAR engineering
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