Strategies to Genetically Modulate Dendritic Cells to Potentiate Anti-Tumor Responses in Hematologic Malignancies

Cornel, Annelisa M.; Til, Niek P. van; Boelens, Jaap Jan; Nierkens, Stefan

doi:10.3389/fimmu.2018.00982

Cited by 11 publications

(8 citation statements)

References 124 publications

(187 reference statements)

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“…Although FcR-mediated phagocytosis has also been reported to be mechanosensitive 78 , how these receptors are linked to the cytoskeleton is not known. Elucidating the mechanisms of phagocytic mechanosensitivity could enable engineering of dendritic cells or macrophages with improved anti-tumor response 79 or drugbearing particles that evade phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Coupling of β2 integrins to actin by a mechanosensitive molecular clutch drives complement receptor-mediated phagocytosis

2019

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αMβ2 integrin (complement receptor 3) is a major receptor for phagocytosis in macrophages. In other contexts, integrins' activities and functions are mechanically linked to actin dynamics through focal adhesions (FAs). We asked whether mechanical coupling of αMβ2 integrin to the actin cytoskeleton mediates phagocytosis. We found that particle internalization was driven by formation of Arp2/3 and formin-dependent actin protrusions that wrapped around the particle. Focal complex-like adhesions formed in the phagocytic cup that contained β2 integrins, FA proteins and tyrosine kinases. Perturbation of talin and Syk demonstrated that a talin-dependent link between integrin and actin and Syk-mediated recruitment of vinculin enable force transmission to target particles and promote phagocytosis. Altering target mechanical properties demonstrated more efficient phagocytosis of stiffer targets. Thus, macrophages use tyrosine kinase signaling to build a mechanosensitive, talin-and vinculin-mediated, FA-like molecular clutch, which couples integrins to cytoskeletal forces to drive particle engulfment.

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Section: Discussionmentioning

confidence: 99%

Coupling of β2 integrins to actin by a mechanosensitive molecular clutch drives complement receptor-mediated phagocytosis

2019

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“…The first clinical trial on therapeutic cancer vaccine was carried out in 1998 on patients with melanoma [93]. Since the activation of the antigen-presenting ability of DCs is directly related with the induction of the CD8 + T cell response, researchers have focused on the modification of DCs in order to enhance the anti-tumor immune responses in vivo [94–96]. Many studies have demonstrated that most malignant tumors, including lung cancers, can produce a variety of factors that suppress anti-tumor immunity.…”

Section: Progress In the Clinical Application Of DC Function Restorationmentioning

confidence: 99%

Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives

Wang

Huang

2019

Cancer Communications

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Lung cancer is the leading cause of cancer mortality worldwide. Dendritic cells (DCs) are the key factors providing protective immunity against lung tumors and clinical trials have proven that DC function is reduced in lung cancer patients. It is evident that the immunoregulatory network may play a key role in the failure of the immune response to terminate tumors. Lung tumors likely employ numerous strategies to suppress DC-based anti-tumor immunity. Here, we summarize the recent advances in our understanding on lung tumor-induced immunosuppression in DCs, which affects the initiation and development of T-cell responses. We also describe which existing measures to restore DC function may be useful for clinical treatment of lung tumors. Furthering our knowledge of how lung cancer cells alter DC function to generate a tumor-supportive environment will be essential in order to guide the design of new immunotherapy strategies for clinical use.

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“…BM-derived DCs (BMDCs) serve as a model for investigating fundamental mechanisms of DC biology, and more broadly, engineered DCs may constitute the critical material for future cell-based vaccines. A traditional method of differentiating BM cells into DCs involves supplementation with GM-CSF (Cornel et al, 2018;Gundry et al, 2016). However, this does not produce the different physiologically relevant subsets found in vivo.…”

Section: Resultsmentioning

confidence: 99%

Efficient gene knockout in primary human and murine myeloid cells by non-viral delivery of CRISPR-Cas9

Freund¹,

Lock²,

Oh³

et al. 2020

Journal of Experimental Medicine

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Myeloid cells play critical and diverse roles in mammalian physiology, including tissue development and repair, innate defense against pathogens, and generation of adaptive immunity. As cells that show prolonged recruitment to sites of injury or pathology, myeloid cells represent therapeutic targets for a broad range of diseases. However, few approaches have been developed for gene editing of these cell types, likely owing to their sensitivity to foreign genetic material or virus-based manipulation. Here we describe optimized strategies for gene disruption in primary myeloid cells of human and murine origin. Using nucleofection-based delivery of Cas9-ribonuclear proteins (RNPs), we achieved near population-level genetic knockout of single and multiple targets in a range of cell types without selection or enrichment. Importantly, we show that cellular fitness and response to immunological stimuli is not significantly impacted by the gene editing process. This provides a significant advance in the study of myeloid cell biology, thus enabling pathway discovery and drug target validation across species in the field of innate immunity.

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Strategies to Genetically Modulate Dendritic Cells to Potentiate Anti-Tumor Responses in Hematologic Malignancies

Cited by 11 publications

References 124 publications

Coupling of β2 integrins to actin by a mechanosensitive molecular clutch drives complement receptor-mediated phagocytosis

Coupling of β2 integrins to actin by a mechanosensitive molecular clutch drives complement receptor-mediated phagocytosis

Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives

Efficient gene knockout in primary human and murine myeloid cells by non-viral delivery of CRISPR-Cas9

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