Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release

Lian, Shu; Xie, Ruizhi; Ye, Yuying; Xie, Xiaodong; Li, Shuhui; Lu, Yusheng; Li, Bifei; Cheng, Yunlong; Katanaev, Vladimir L.; Jia, Lee

doi:10.1016/j.ebiom.2019.03.018

Cited by 102 publications

(75 citation statements)

References 44 publications

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“…Blocking CD47 also increases the reactivity of anti-tumor T and NK cells and increases the release of various cytokines, including IFN-γ and IL-6. Moreover, the simultaneous blocking of CD47 and PD-1 can further prevent the immune escape of circulating tumor cell subsets, thereby inhibiting metastasis [161,162]. Rodríguez-Ruiz et al proposed that combined anti-PD1 and anti-CD137 treatment increases granzyme-B secreted by CTLs, indicating an improved cytotoxic effect [163].…”

Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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“…Synergetic benefits of targeting multiple receptors are being evidenced including simultaneous blocking of CD47 and PD-L1 in cancer immune responses and cytokine release 55 and dual antibody blockade of CD39 and CD73 combined with ICIs and chemotherapies 56 . CD11b activation is required for macrophage activation and tumor cell phagocytosis 57 .…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells

et al. 2020

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Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.

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“…Additional strategies may synergize with current mAb therapy/ICI therapy by reducing the NK cell activation threshold. This could be achieved by masking tumor checkpoint ligands [i.e., anti-PD-L1, Avelumab, which can also initiate NK cell ADCC (69,120,169,261,278,279), or the TIGIT ligands CD112/CD155 (105,280,281)], activating NK cells in-situ with cytokine variants, and modulating tumors via bio-chemical modifications or inhibitors, making them more susceptible to NK cell-mediated lysis.…”

Section: Sensitizing Tumors For Nk Cell Killingmentioning

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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Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release

Cited by 102 publications

References 44 publications

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells

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

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