Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells

Raulet, David H.; Marcus, Assaf; Coscoy, Laurent

doi:10.1111/imr.12600

Cited by 50 publications

(42 citation statements)

References 84 publications

(217 reference statements)

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“…Moreover, NKG2D ligands are abundantly overexpressed in several human malignancies (88)(89)(90)(91)(92)(93) and sensitize tumors to NK cell-mediated killing (94)(95)(96)(97)(98)(99). Thus, it comes as no surprise that tumors employ a wide array of mechanisms to modulate NKG2D ligand expression to escape NK cell immune surveillance (100)(101)(102)(103)(104)(105)(106). Additional approaches to the one we describe here, have focused on developing therapeutics that increase the expression of NKG2D on NK cells (27,107,108) or enhance the expression levels of NKG2D ligands, as has been tested for Ewing sarcoma cell lines (109,110).…”

Section: Discussionmentioning

confidence: 99%

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

et al. 2020

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Sayitoglu et al. Boosting NK Cell-Mediated Sarcoma Targeting cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1 + or NKG2D + GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

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Section: Discussionmentioning

confidence: 99%

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

et al. 2020

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“…Additional therapeutic approaches harness chemical compounds that induce the expression of NK cell-activating ligands on tumors, or that inhibit tumor pathways promoting NK cell immunosuppression (306). Such strategies may increase tumor susceptibly to immune surveillance, and synergize with current therapies such as mAb treatment and checkpoint blockade, since downregulation of activating ligands promotes tumor escape (29).…”

Section: Upregulation Of Nk Cell Ligandsmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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“…NK cells derived from NK cell lines, donor or autologous peripheral blood mononuclear cell (PBMC) and umbilical cord blood have been modified to express CARs against different cancer targets, including CD7, CD19, CD22, CD33 for lymphoma and leukemia, HER2 for glioblastoma, MUC1 for HCC (NCT02839954) and NKG2D for metastatic solid tumors (NCT03415100) [10,78,79]. Importantly, NK cells express activating receptors, such as NCRs, NKG2D, and DNAM-1 which are rapidly triggered by engagement of ligands expressed by stressed and transformed cells [80]. The naturally occurring cytotoxicity mediated by NK cells can complement CAR-induced cell killing and may allow CAR-NK cells to bypass the loss of targeted antigens as a tumor escape mechanism [81].…”

Section: Nkg2d Based Car-nk Cellsmentioning

confidence: 99%

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Mantovani

Oliviero

Varchetta

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri-and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

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Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells

Cited by 50 publications

References 84 publications

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

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