Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Capuano, Cristina; Pighi, Chiara; Battella, Simone; Federicis, Davide De; Galandrini, Ricciarda; Palmieri, Gabriella

doi:10.3390/cancers13102500

Cited by 48 publications

(30 citation statements)

References 248 publications

(353 reference statements)

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“…Combining adoptive NK cell therapy with daratumumab is an interesting approach to circumvent the acquired immune suppression in MM patients. The presence of CD16a, the low-affinity receptor for IgG1 and IgG3, on the surface of NK-cells is crucial for ADCC-dependent cell killing by tumor-targeting mAbs [ 32 ]. Depending on the expansion and culture conditions, this CD16a expression can decrease, but the combined use of expanded NK-cells (from umbilical cord blood or peripheral blood) with daratumumab shows encouraging results in preclinical studies [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

Lejeune

Duray

Peipp

et al. 2021

Cancers

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Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In this study, we correlated the NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and potential fratricide induced by daratumumab with CD38-expression levels on both effector and target cells. We show that CD38 expression can be modulated by adding all-trans retinoic acid (ATRA) or interferon-α to MM cells to further fine-tune these effects. In addition, we observed that ADCC becomes inefficient when fratricide occurs and both ADCC and fratricide depend on the balance between CD38 expression on effector and target cells. However, the addition of adjuvants (retinoic acid or interferon-α) to myeloma cells or the inhibition of fratricide using a CD38-blocking nanobody on NK-cells can reverse this balance towards ADCC and thus promote lysis of target cells by ADCC. ATRA and interferon-α increased the CD38 expression at the surface of MM cells about three-fold and two-fold, respectively. This increase was of interest for MM cells with low CD38 expression, that became susceptible to daratumumab-mediated ADCC after preincubation. A CD38-blocking nanobody prevented the binding of daratumumab to these NK-cells and blunted the fratricidal effect on effector NK cells. In conclusion, our study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated ADCC.

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Section: Discussionmentioning

confidence: 99%

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

Lejeune

Duray

Peipp

et al. 2021

Cancers

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“…Additionally, it has also been proposed that under specific chronic inflammatory conditions of cancer, TAMs protect tumour cells from NK cytotoxicity by preventing the shedding of membrane-bound CD16 ( 108 ). CD16 is an Fc receptor whose shedding indicates NK cell activation and increases NK engagement with target cells ( 109 ). While the maintenance of surface CD16 indicates inhibition of NK cell function, it is worth noting that simultaneously, CD16 acts as an important activating receptor in antibody-dependent cytotoxicity, and it is a well-explored therapeutic target ( 110 ).…”

Section: Context-specific Mechanisms Driving Altered Nk Cell Phenotypes In the Tumour Microenvironmentmentioning

confidence: 99%

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021

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Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.

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“…NK cells are the ideal candidate for adoptive therapy combined with mAbs targeting specific tumor antigens due to their unique mechanism of target cell lysis through ADCC mediated by their CD16 (FcγRIIIa) receptors ( 20 ). Multiple preclinical studies have shown the benefit of NK cells and mAbs in pediatric sarcomas ( 21 – 23 ).…”

Section: Therapeutic Enhancement Of Nk Cell Functions Via Adccmentioning

confidence: 99%

“…Inclusion criteria based on the presence of predictive biomarkers identifying patients who would likely respond to these mAb are needed to determine the utility of these agents. The clinical response to mAb is also affected by a single nucleotide polymorphism in the FCGR3A (CD16) gene that affects binding affinity for IgG (increased affinity with valine at FCGR3A-158) ( 20 ).…”

Section: Therapeutic Enhancement Of Nk Cell Functions Via Adccmentioning

confidence: 99%

“…Even though the mAbs bind to the activating receptor CD16 on NK cells, a potent activating signal, they have not shown positive results in pediatric sarcoma ( 20 ). Combination with adoptive NK cell therapy, small molecules or other strategies to amplify ADCC, as well as a better selection of patients to include in trials based on their tumor expression profile, could improve the mAbs efficacy.…”

Section: Therapeutic Enhancement Of Nk Cell Functions Via Adccmentioning

confidence: 99%

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Enhancing Natural Killer Cell Targeting of Pediatric Sarcoma

et al. 2021

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Osteosarcoma, Ewing sarcoma (EWS), and rhabdomyosarcoma (RMS) are the most common pediatric sarcomas. Conventional therapy for these sarcomas comprises neoadjuvant and adjuvant chemotherapy, surgical resection of the primary tumor and/or radiation therapy. Patients with metastatic, relapsed, or refractory tumors have a dismal prognosis due to resistance to these conventional therapies. Therefore, innovative therapeutic interventions, such as immunotherapy, are urgently needed. Recently, cancer research has focused attention on natural killer (NK) cells due their innate ability to recognize and kill tumor cells. Osteosarcoma, EWS and RMS, are known to be sensitive to NK cell cytotoxicity in vitro. In the clinical setting however, NK cell cytotoxicity against sarcoma cells has been mainly studied in the context of allogeneic stem cell transplantation, where a rapid immune reconstitution of NK cells plays a key role in the control of the disease, known as graft-versus-tumor effect. In this review, we discuss the evidence for the current and future strategies to enhance the NK cell-versus-pediatric sarcoma effect, with a clinical focus. The different approaches encompass enhancing antibody-dependent NK cell cytotoxicity, counteracting the NK cell mechanisms of self-tolerance, and developing adoptive NK cell therapy including chimeric antigen receptor-expressing NK cells.

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Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Cited by 48 publications

References 248 publications

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

Enhancing Natural Killer Cell Targeting of Pediatric Sarcoma

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