Converting Lymphoma Cells into Potent Antigen-Presenting Cells for Interferon-Induced Tumor Regression

Liao, Jing; Luan, Yan; Ren, Zhenhua; Liu, Xiaojuan; Xue, Diyuan; Xu, Hairong; Sun, Zhichen; Yang, Kaiting; Peng, Hua; Fu, Yang Xin

doi:10.1158/2326-6066.cir-16-0221

Cited by 14 publications

(10 citation statements)

References 39 publications

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“…Systemic delivery of type I IFNs is usually used clinically, but high-dose need to be administrated to achieve high-serum concentration for effective therapeutic effect accompanied with dose-limiting toxicities. Arming tumor-targeting antibodies with cytokines has been shown to be a potent strategy for the local delivery of immunomodulatory molecules 19 – 22 . However, it is difficult to identify tumor-specific molecules for therapeutic targeting.…”

Section: Resultsmentioning

confidence: 99%

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

et al. 2018

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Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.

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Section: Resultsmentioning

confidence: 99%

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

et al. 2018

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“…Fibrotic tissue and normal thyroid tissue were consistent with echogenic structures within or around the lesions. Densely and uniformly proliferated lymphoma cells in the lesion were possibly related with an enhanced posterior echo [40]. HT is considered as a risk factor for thyroid lymphoma development.…”

Section: Discussionmentioning

confidence: 90%

Is ultrasound combined with computed tomography useful for distinguishing between primary thyroid lymphoma and Hashimoto’s thyroiditis?

Luo

Huang

Zhou

et al. 2019

Endokrynologia Polska

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Introduction: The aim of the study is to investigate the usefulness of ultrasound combined with computed tomography (CT) for distinguishing between primary thyroid lymphoma (PTL) and Hashimoto's thyroiditis (HT). Material and methods: The investigation was conducted retrospectively in 80 patients from January 2000 to July 2018. All patients underwent pathological tests to be classified into one of two groups: PTL group and HT group. The cutoff value of CT density was determined using receiver-operating characteristic (ROC) curve analysis. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of diagnosis for thyroid by CT alone, ultrasound alone, and the combination of CT plus ultrasound were calculated. Results: Of the 80 study patients, 27 patients were PTL and 53 patients were HT. Mean CT density had a sensitivity of 90.6% and a specificity of 88.9% at a cutoff value of 53.5 HU, with area under the curve (AUC) 0.88. Ultrasound combined with CT had the highest specificity, accuracy, and PPV compared with CT alone and ultrasound alone (p value < 0.05). Conclusions: Features such as extremely hypoechogenicity, enhanced posterior echo, cervical lymphadenopathy in ultrasound image, and linear high-density strand signs, and very low density in CT imaging have high sensitivity and specificity in thyroid lymphoma. Therefore, ultrasound combined with CT may be useful for distinguishing between PTL and HT.

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“…However, the function of IFNAR on host immune cells was not addressed. Using a syngeneic immunocompetent mouse model, Liao et al observed that targeting lymphoma with IFNα abolished resistance of B-cell lymphoma to anti-CD20 Ab while also limiting interferon (IFN)-associated systemic toxicity in the host (Liao et al 2017 ). Anti-CD20–IFNα fusion protein-mediated tumor control is dependent on existing tumor-infiltrating CD8+ T cells.…”

Section: Antibody Armed With Cytokines To Further Promote Adaptive Anmentioning

confidence: 99%

“…But the mechanism is unclear. In another combination therapy, PD-L1 blockade could enhance the antitumor efficacy of anti-CD20–IFNα and reduce relapse rates for advanced large tumors that are resistant to either anti-CD20 Ab or the anti-CD20–IFNα fusion protein (Liao et al 2017 ). IFN can increase PD-L1 expression on tumor cells and antigen presentation, each of which represents distinct mechanism of tumor control.…”

Section: Antibodies Targeting To Immune Inhibitory Receptors and Combmentioning

confidence: 99%

Targeting tumor cells with antibodies enhances anti-tumor immunity

Sun

Peng

2018

Biophys Rep

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Tumor-targeting antibodies were initially defined as a group of therapeutic monoclonal antibodies (mAb) that recognize tumor-specific membrane proteins, block cell signaling, and induce tumor-killing through Fc-driven innate immune responses. However, in the past decade, ample evidence has shown that tumor-targeting mAb (TTmAb) eradicates tumor cells via activation of cytotoxic T cells (CTLs). In this review, we specifically focus on how TTmAbs induce adaptive anti-tumor immunity and its potential in combination therapy with immune cytokines, checkpoint blockade, radiation, and enzyme-targeted small molecule drugs. Exploring the mechanisms of these preclinical studies and retrospective clinical data will significantly benefit the development of highly efficient and specific TTmAb-oriented anti-tumor remedies.

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Converting Lymphoma Cells into Potent Antigen-Presenting Cells for Interferon-Induced Tumor Regression

Cited by 14 publications

References 39 publications

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

Is ultrasound combined with computed tomography useful for distinguishing between primary thyroid lymphoma and Hashimoto’s thyroiditis?

Targeting tumor cells with antibodies enhances anti-tumor immunity

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