Distinct Patterns of PD-L1 and PD-L2 Expression By Tumor and Non-Tumor Cells in Patients with MM, MDS and AML

Dail, Monique; Yang, Long; Green, Cherie; Ma, Connie; Robert, Alberto; Kadel, Edward E.; Koeppen, Harmut; Adamkewicz, Joanne I.; Byon, John; Woodard, Joseph; Rodig, Scott J.; Venstrom, Jeffrey M.

doi:10.1182/blood.v128.22.1340.1340

Cited by 13 publications

(13 citation statements)

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“…This upregulation of PD-1/PD-L1 is evident not only in the clonal cells but also in their surrounding mesenchymal cells. Dail et al [ 47 ] measured PD-L1 expression using multicolor flow cytometry and immunohistochemistry and found that PD-L1 is detectable in more than 2% of cells in all MDS patients, with the majority of expression occurring in non-tumor hematopoietic cells. This supports that the upregulation of PD-1/PD-L1 occurs in both clonal cells and MSC.…”

Section: Mds and Checkpoint Inhibitorsmentioning

confidence: 99%

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

Chokr

Patel

Wattamwar

et al. 2018

Advances in Hematology

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Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy.

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Section: Mds and Checkpoint Inhibitorsmentioning

confidence: 99%

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

Chokr

Patel

Wattamwar

et al. 2018

Advances in Hematology

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“…PD-L1, programmed death-ligand 1; PBMC, peripheral blood mononuclear cells; EGT, epigenetic therapy; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.. response to EGT, NUR77 suggesting enhanced PD-L1 expression and associated downstream molecular mechanisms may be a more potent phenotypic contributor to EGT outcomes than potential response biomarkers including NUR77. Whilst previous studies have demonstrated EGT is able to increase PD-L1 expression in MDS (16)(17)(18) and may correlate with poor responses to treatment (18) our study is the first to identify this effect independent of potential response marker expression. Whilst our in vivo observations support our in vitro findings a potential limitation of our study exists due to logistical constraints in obtaining chronologically identical patient blood samples for analysis during cycle 1.…”

Section: Discussionmentioning

confidence: 53%

“…EGT. PD-L1 reverse signaling has recently been identified as a potential mechanism of EGT resistance in the setting of MDS treatment (8,(16)(17)(18)(19). We investigated the in vitro and in vivo effect of EGT on potential down-stream effector molecules of reverse PD-L1 signaling.…”

Section: Kg-1 Cells and In Patients Non-responsive And Responsive Tomentioning

confidence: 99%

Epigenetic treatment‑mediated modulation of PD‑L1 predicts potential therapy resistance over response markers in myeloid malignancies: A molecular mechanism involving effectors of PD‑L1 reverse signaling

Liu

Rimoldi

et al. 2018

Oncol Lett

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Recent evidence suggests an association exists between resistance to epigenetic therapy (EGT) and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in myeloid malignancies. Biomarkers are required to predict resistance to EGT in myeloid malignancies, which together with the delineation of associated molecular mechanisms, may provide additional understanding for novel treatment strategies when investigating resistance to EGT. The present study aimed to investigate the in vivo effects of EGT on the expression of PD-1, PD-L1 and orphan nuclear receptor NUR77 with clinical responses in patients with myeloid malignancies. In addition, in vitro and in vivo characterization of the effects of EGT on the expression of NF-κB and Bcl-xL, potential downstream targets of PD-L1 reverse signaling, were evaluated to determine components of the molecular mechanism responsible for these effects. The in vivo effects of EGT on the expression of PD-1, PD-L1 and a previously identified molecular marker of response to EGT, NUR77 was characterized in peripheral blood mononuclear cells (PBMC) from patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with either azacytidine (Aza) alone or a combination of Aza and the histone deacetylase inhibitor (HDACi) LBH-589 during the first cycle of therapy. The correlation of clinical responses to treatment with EGT with the expression of PD-1, PD-L1 and NUR77 demonstrated that the induction of PD-L1 mRNA levels was associated with resistance to EGT despite the concurrent augmentation of NUR77 expression. The characterization of potential downstream effector molecules of reverse PD-L1 signaling identified EGT-mediated induction of Bcl-xL and NF-κB mRNA expression in vitro and in vivo, suggesting a potential anti-apoptotic molecular mechanism was responsible for PD-L1-mediated resistance to EGT. Taken together, these observations suggest that enhanced PD-L1 expression may confer resistance to EGT over known EGT response markers in myeloid malignancies, and provides a potential molecular mechanism involving the modulation of effectors of PD-L1 reverse signaling, which may in-part, be responsible for these effects.

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“…PD-L1 is extremely rampant in multiple myeloma (MM), myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML), with considerable expression by non-tumor hematopoietic cells, mainly CD8+ T-cells ( 23 ). PD-L2 expression is considerably absent in myeloid diseases but detectable in MM ( 24 ). Interestingly, PD-L1 expression is most common on TCs in MM and on non-tumor hematopoietic cells in MDS, while expression on non-tumor and TCs in AML was comparable ( 25 ).…”

Section: Immune Checkpoint Moleculesmentioning

confidence: 99%

Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles

Cho

2017

Immune Netw

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Lung cancer is one of the leading causes of death worldwide. There are 2 major subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Studies show that NSCLC is the more prevalent type of lung cancer that accounts for approximately 80%–85% of cases. Although, various treatment methods, such as chemotherapy, surgery, and radiation therapy have been used to treat lung cancer patients, there is an emergent need to develop more effective approaches to deal with advanced stages of tumors. Recently, immunotherapy has emerged as a new approach to combat with such tumors. The development and success of programmed cell death 1 (PD-1)/program death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades in treating metastatic cancers opens a new pavement for the future research. The current mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells. Additionally, this review also addresses the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy. Immunotherapy can be a promising approach to treat NSCLC because it stimulates host's own immune system to recognize cancer cells. Therefore, future research should focus on the development of new methodologies to identify novel checkpoint inhibitors and potential neoantigens.

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Distinct Patterns of PD-L1 and PD-L2 Expression By Tumor and Non-Tumor Cells in Patients with MM, MDS and AML

Cited by 13 publications

References 0 publications

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

Epigenetic treatment‑mediated modulation of PD‑L1 predicts potential therapy resistance over response markers in myeloid malignancies: A molecular mechanism involving effectors of PD‑L1 reverse signaling

Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles

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