PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines

Peng, Weiyi; Liu, Chengwen; Xu, Chunyu; Lou, Yanyan; Chen, Jieqing; Yang, Yan; Yagita, Hideo; Overwijk, Willem W.; Lizée, Gregory; Radvanyi, Laszlo G.; Hwu, Patrick

doi:10.1158/0008-5472.can-12-1187

Cited by 374 publications

(305 citation statements)

References 38 publications

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“…We found both in vitro and in vivo that blocking PD-1 significantly enhanced the function of CAR T cells leading to a more lethal hit against the tumor. Unlike other studies that used MHC class I restricted T cells (26,27), we found no increase in the percentage of adoptively transferred Thy1.1 þ T cells in the blood or tumor site following combined therapy compared with control treated mice. Future studies using other qualitative approaches such as luciferase transduced T cells would enable the kinetics of T-cell infiltration to be better defined (27).…”

Section: Discussioncontrasting

confidence: 99%

“…Unlike other studies that used MHC class I restricted T cells (26,27), we found no increase in the percentage of adoptively transferred Thy1.1 þ T cells in the blood or tumor site following combined therapy compared with control treated mice. Future studies using other qualitative approaches such as luciferase transduced T cells would enable the kinetics of T-cell infiltration to be better defined (27). An interesting aspect of the current study was that the strong antitumor effects observed with CAR T cells combined with anti-PD-1 antibody correlated with a significant decrease in the percentage of Gr-1 þ CD11b þ MDSCs at the tumor site.…”

Section: Discussioncontrasting

confidence: 99%

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Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells

John

Devaud

Duong

et al. 2013

Clinical Cancer Research

616

430

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Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression.Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2 þ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach.Results: In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8 þ T cells following antigen-specific stimulation with PD-L1 þ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2 þ tumors treated with anti-Her-2 T cells in combination with anti-PD-1antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1 þ CD11b þ myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. Conclusion: This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells

John

Devaud

Duong

et al. 2013

Clinical Cancer Research

616

430

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“…Anti-PD-1 mAb after the first injection resulted in partial tumor regression (1/5 mice in anti-PD-1 mAbþp24 fc /EP group and 2/5 mice in anti-PD-1 mAb alone group, respectively; ref. 25). However, this effect was abolished when tumor developed in large volume during second and third vaccination.…”

Section: Therapeutic Cure Of Mesothelioma By Vaccine-elicited Immune mentioning

confidence: 96%

Vaccine-Elicited CD8+ T Cells Cure Mesothelioma by Overcoming Tumor-Induced Immunosuppressive Environment

et al. 2014

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Eradicating malignant tumors by vaccine-elicited host immunity remains a major medical challenge. To date, correlates of immune protection remain unknown for malignant mesothelioma. In this study, we demonstrated that antigen-specific CD8 þ T-cell immune response correlates with the elimination of malignant mesothelioma by a model PD-1-based DNA vaccine. Unlike the nonprotective tumor antigen WT1-based DNA vaccines, the model vaccine showed complete and long-lasting protection against lethal mesothelioma challenge in immunocompetent BALB/c mice. Furthermore, it remained highly immunogenic in tumor-bearing animals and led to therapeutic cure of preexisting mesothelioma. T-cell depletion and adoptive transfer experiments revealed that vaccine-elicited CD8 þ T cells conferred to the protective efficacy in a dose-dependent way. Also, these CD8

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“…Both ILs have been shown to be induced in cuprizonefed animals (81,82). (84), generates a Th1-favored, proinflammatory response (85), appears to be involved in NK cell recruitment (86), drives plasma cell differentiation (87), and has been linked to the trafficking of immune cells into malignant disease sites (88). Furthermore, CXCL10 can inhibit vascular smooth muscle cell proliferation (89), or endothelial cell proliferation in vitro independently of CXCR3 (90).…”

Section: Significance Of the Study Using The Cuprizone Modelmentioning

confidence: 99%

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

Clarner

Janssen

Nellessen

et al. 2015

The Journal of Immunology

118

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A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

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PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines

Cited by 374 publications

References 38 publications

Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells

Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells

Vaccine-Elicited CD8+ T Cells Cure Mesothelioma by Overcoming Tumor-Induced Immunosuppressive Environment

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

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