Trends in Immunology
ForumInhibition-Resistant CARs for NK Cell Cancer Immunotherapy
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.
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Immunogenomics of Killer Cell Immunoglobulin-Like Receptor (KIR) and HLA Class I: Coevolution and Consequences for Human Health
2022, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :Nevertheless, effect differences remain across transplant centers or treatment regimens,191 and further refinement of matching protocols will likely be aided through refinement of the genotyping methods.192,193 The previous findings, together with the established links between peripheral NK cell quantity and disease course, also imply that NK cells can be harnessed to treat autoimmune and other chronic diseases, as they have for malignancies.194-197 That presence of KIR3DS1 is significantly associated with resistance to PD-1 blockade,198 for example, and KIR3DL1 interaction with Bw4+HLA affects monoclonal antibody therapy199,200 demonstrates that knowledge of the receptor and ligand genotype may also inform these therapy decisions.201
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