Regulation of Programmed Death Ligand 1 (PD-L1) Expression in Breast Cancer Cell Lines In Vitro and in Immunodeficient and Humanized Tumor Mice

Rom-Jurek, Eva-Maria; Kirchhammer, Nicole; Ugocsai, Peter; Ortmann, O.; Wege, Anja K.; Brockhoff, Gero

doi:10.3390/ijms19020563

Cited by 53 publications

(46 citation statements)

References 37 publications

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“…This observation is consistent with the observed growth‐inhibitory effect of PD1 blockade in HIS mice (Wang et al ., ) and indicates that the MDA‐MB‐231 model may prove valuable for evaluating combination partners to PD1/PDL1 blockade, and possibly also treatments directed toward relieving the immune suppressive capacity of human Tregs. It is noteworthy that another group recently reported no effect on MDA‐MB‐231 PDL1 expression when transplanted subcutaneously in HIS mice (Rom‐Jurek et al ., ). Whether this apparent discrepancy is due to differences in transplantation sites or the extent of the immune responses within each mouse warrants further investigations.…”

Section: Discussionmentioning

confidence: 99%

Human cancer evolution in the context of a human immune system in mice

et al. 2018

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Immunotherapy is one of the most promising cancer treatment modalities, but the lack of appropriate preclinical in vivo models hampers the development of novel immunotherapeutic strategies. Here, we studied the ability of transplanted human cancer cells to form primary tumors and metastasize in humanized immune system (HIS) mice created by transfer of CD34+ human hematopoietic stem cells. All tested transplanted cancer cell lines developed primary tumors that progressed nearly synchronously. Spontaneous lung and liver metastases developed from both orthotopic and ectopic transplanted cancer cells, and the ability to spread inversely correlated with the extent of CD8+ infiltration in the primary tumor. Further analysis revealed that interactions between the cancer model and the tumor‐infiltrating lymphocytes created tumor microenvironments (TMEs) resembling clinical cancers. Some models were largely immune cell‐excluding, while others appeared to develop adaptive resistance to immune‐mediated destruction by increased expression of programmed death ligand 1 (PDL1) and recruitment of human regulatory T cells. Our data suggest that HIS mice may provide a promising in vivo tumor model for evaluating immune modulatory anticancer therapies. Moreover, our study identified different tumor models resembling specific types of human TMEs, rendering each beneficial for addressing disease‐specific issues.

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Section: Discussionmentioning

confidence: 99%

Human cancer evolution in the context of a human immune system in mice

et al. 2018

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“…We next investigated whether the ability of RSV to target PD-L1 glycosylation altered PD-L1 membrane trafficking. Light microscopy observations suggested that RSV induced a hypertrophy-like phenotype in treated JIMT-1 and MDA-MB-231 cells ( Figure 6, top panels), a second PD-L1-overexpressing breast cancer model representative of the basal-like subtype [40,67,68] as indicated by the transformation of spindle-shaped control cells to more enlarged, irregular, and flattened cell morphologies after switching to culture medium with RSV ( Figure 6, top panels). Also, immuno-fluorescence microscopy using an antibody directed against an intracellular epitope of PD-L1 showed PD-L1 enrichment both in the plasma membrane and in specific cytoplasmic vesicular-like compartments ( Figure 6, bottom panels).…”

Section: Resveratrol Inhibits the Cell Membrane Localization Of Glycomentioning

confidence: 99%

“…Here, we took advantage of the JIMT-1 cell line, a unique model of highly-aggressive basal-like/HER2-positive breast cancer naturally overexpressing the immunosuppressive molecule PD-L1 with 100% of the cells positive for PD-L1 [40], to explore the potential regulatory effects of mechanistically diverse metabolismtargeting drugs on PD-L1. By combining biochemical, computational, and microscopy approaches with labelfree monitoring of T-cell activation, we provide the first evidence that the dietary polyphenol resveratrol (RSV) can directly target PD-L1 glycosylation and dimerization to enhance anti-tumor T-cell immunity.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Verdura

Cuyàs

Cortada

et al. 2020

Aging

117

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New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.

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“…3C). It is reported that paclitaxel treatment is also able to induce PD-L1 expression in tumor cells, including the TNBC cell line MDA-MB-231 and a panel of ovarian cell lines (45)(46)(47). Therefore, we investigated PD-L1 levels in CD45 − CD49f + KBP mammary tumor cells as we did in TAMs.…”

Section: Ros-induced Pd-l1 Expression Is Mediated By the Transcriptionmentioning

confidence: 99%

Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1

Roux

Jafari

Shinde

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

152

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The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti–PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.

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Regulation of Programmed Death Ligand 1 (PD-L1) Expression in Breast Cancer Cell Lines In Vitro and in Immunodeficient and Humanized Tumor Mice

Cited by 53 publications

References 37 publications

Human cancer evolution in the context of a human immune system in mice

Human cancer evolution in the context of a human immune system in mice

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1

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