Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance

Willimsky, Gerald; Schmidt, Karin; Loddenkemper, Christoph; Gellermann, Johanna; Blankenstein, Thomas

doi:10.1172/jci64742

Cited by 46 publications

(48 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine the potential effect of PD-1:28 tm on tumor progression, a murine model of autochthonous HCC was used where tumors develop after activation of the SV40-TAg (28). This tumor model resembles the human situation in its slow course of tumor progression, spanning up to 35 weeks from initiating the oncogenic process until death from tumor load.…”

Section: Discussionmentioning

confidence: 99%

“…The following cell lines were used: HEK293 cells (positive for HLA-A2, negative for endogenous PD-L1 by flow cytometry, obtained from H. Engelmann, Institute of Immunology, Munich, Germany, in 1997) were transduced in our laboratory to express tyrosinase (HEK/Tyr) or tyrosinase and PD-L1 (HEK/Tyr/PD-L1). Single-cell clones were selected for comparable HLA-A2 and tyrosinase expression ( Murine hepatocellular carcinoma (HCC) line 434 originated in LoxP-TAg mice (28) and was grown in RPMI-basic/12% FCS/0.05% b-mercaptoethanol (mouse medium). Authentication was done by testing SV40LT, H2-D b , and PD-L1 expression.…”

Section: Cell Lines Pbmcs and Tilsmentioning

confidence: 99%

See 1 more Smart Citation

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

et al. 2017

Self Cite

View full text Add to dashboard Cite

Inherent intermediate-to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNg compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. Ó2017 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cell Lines Pbmcs and Tilsmentioning

confidence: 99%

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…PD-1/PD-L1 expression has been documented in surgical specimens from resected HCCs. Willimsky et al reported PD-L1 expression in HCC cells and PD-1 expression in CD8 + T cells [33]. Similarly, Sawada et al showed that PD-1 is highly expressed on the CTLs of patients vaccinated with GPC3 [34].…”

Section: Pd-1mentioning

confidence: 97%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

show abstract

“…Antigen-specific local tolerance allowing HCC progression in this model was partially mediated by interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1, because we found that Tag-specific T cells express PD-1 and the virus-induced HCC the respective ligand PD-L1. 11 Another conclusion from the current study is that tumor-reactive CTL, functionally activated in the course of viral infection, are not down-regulated by iMC, which expand because of HCC development subsequent to viral Tag activation.…”

Section: Discussionmentioning

confidence: 63%

“…Note that tumor cell lines from all 3 models had a regressor phenotype in transplantation experiments. 8,10,11 Surprisingly, the apparently most suppressive iMC population, CD11b…”

Section: Discussionmentioning

confidence: 99%

Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer

Schmidt

Zilio

Schmollinger

et al. 2013

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance

Cited by 46 publications

References 63 publications

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer

Contact Info

Product

Resources

About