Trends in Immunology

Trends in Immunology

Volume 40, Issue 12, December 2019, Pages 1078-1081
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Inhibition-Resistant CARs for NK Cell Cancer Immunotherapy

https://doi.org/10.1016/j.it.2019.10.004Get rights and content

The promise of natural killer (NK) cells as effectors in cancer cellular therapy is limited by their expression of dominant inhibitory receptors for human leukocyte antigen (HLA) class I. Here, we discuss how chimeric antigen receptors (CARs) engineered to override inhibitory signaling might boost NK cell antitumor responses, independently of blockade of NK cell inhibitory receptors.

Section snippets

Cancer Immunotherapy with Cytotoxic Lymphocytes

Infusion of chimeric antigen receptor (CAR)-expressing autologous CD8+ cytotoxic T lymphocytes (CAR-T cells) has been remarkably effective in treating certain refractory cancers [1]. However, adverse effects, such as cytokine release syndrome (CRS) and neurotoxicity, can be life threatening. To overcome the limitations of obtaining large numbers of autologous cytotoxic T lymphocytes (CTL) and simplify the process of producing CAR-T cells, strategies based on ‘off-the-shelf’ CAR-T cells have

Integrated Activation and Inhibition Receptor Signaling Controls NK Cell Responses

NK cell cytotoxicity toward cancer cells requires signals from an integrin to adhere to target cells, in combination with signals from several activation receptors for polarized release of lytic granule effector molecules [5]. Some tumor cells express ligands of NK cell activation receptors and become targets of NK-mediated lysis, which does not require priming by prior encounter with tumor antigens. However, NK cells are tightly controlled by inhibitory receptors for HLA class I, including the

Immunotherapy with NK Cells: Overcoming Inhibition by HLA Class I-Specific Receptors

Downregulation of HLA class I expression occurs in some tumor cells, rendering them resistant to CTL, but vulnerable to NK-mediated killing. However, most tumor cells express sufficient HLA class I to inhibit NK cells. Chronic inflammation in tumors may promote IFN-γ-induced HLA class I expression, leading to resistance to NK cells. The high proportion of NKG2A+ NK cells – higher following transplantation or ex vivo expansion [7] – coupled to HLA-E upregulation in certain tumors [8], emphasizes

Signals Required to Overcome Tumor Cell Resistance

Tumor cells may resist NK cell attack due to insufficient NK–target cell adhesion, lack of tumor cell ligands that engage NK cell activation receptors, or expression of HLA-I ligands that bind NK cell inhibitory receptors. In many cases, the basis for tumor cell resistance against NK cell attack is unknown. Studies have reported that CAR expression in NK cells can overcome tumor cell resistance [13,14]. A CD19-CAR in NK cells induced killing of several B lineage acute lymphoblastic leukemia

NK-Tailored CARs: Overcoming Inhibition to Promote Antitumor NK Cell Activity

Two recent studies directly tested the functional activity of CAR-NK cells in the context of inhibition mediated by HLA-E-specific NKG2A or HLA-C-specific KIRs [15,16]. In the first study, IL-15-activated human peripheral blood NK cells, expressing a CD19-directed CAR with a CD28-OX40-TCRζ signaling domain, were tested [15]. Untransfected NK cells were inhibited by ectopically-expressed HLA-E on HLA class I negative CD19+ B cells (721.221 cell line). However, the CAR-NK cells could

Concluding Remarks

We favor the concept that NK cell cytotoxic activity can be repurposed to selectively kill cancer cells when triggered by tumor-specific CARs. However, the constraint placed on NK cells by HLA class I inhibitory receptors has to be considered for this approach. A strategy that would obviate pharmacological blockade or genetic disabling of inhibitory receptors is to engineer CARs that can either overwhelm, or bypass inhibitory signaling (Figure 1). A significant benefit might be that such CAR-NK

Acknowledgments

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH grant 1ZIAAI000525-31.

References (16)

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