Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

Liu, Juan; Quan, Lina; Zhang, Chunhui; Liu, Aichun; Tong, Dongxia; Wang, Jinghua

doi:10.3892/ol.2017.7682

Cited by 17 publications

(19 citation statements)

References 17 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis, which plays an important role both in transplanted organ tolerance and in antitumour immune responses, has been studied in different haematological neoplasms . Nevertheless, its clinical and biological significance in PTLD is largely unknown …”

Section: Introductionmentioning

confidence: 99%

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

et al. 2019

View full text Add to dashboard Cite

Aims The clinical implications of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in patients with post‐transplant lymphoproliferative disorders are largely unknown, and its association with Epstein–Barr virus (EBV) status and PD‐L1 copy number alterations (CNAs) has not been thoroughly studied. Methods and results PD1/PD‐L1 expression was studied in 50 adult post‐transplant lymphoproliferative disorders, and the correlations with PD‐L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty‐seven (74%) cases were classified as diffuse large B‐cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty‐four cases were EBV‐positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD‐L1 expression in tumour cells and tumour‐associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD‐L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non‐germinal centre type DLBCL (P < 0.001). Cases with PD‐L1‐positive tumour cells showed a higher number of PD‐L1 CNAs than PD‐L1‐negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD‐L1 expression showed the worst overall survival (P < 0.001). Conclusions The PD1/PD‐L1 axis is deregulated in post‐transplant lymphoproliferative disorders, with frequent PD‐L1 expression and PD1 negativity. PD‐L1 expression is associated with EBV latency II or III and PD‐L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD‐L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

show abstract

Section: Introductionmentioning

confidence: 99%

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

et al. 2019

View full text Add to dashboard Cite

show abstract

“…23 Another possible reason is that chemotherapeutic resistance may arise from positive PD-L1 expression partly, which may link to poor prognosis. 21 These findings suggest that PD-L1 expression may be favorable to discover GDLBCL patients who have a high disease progression risk.…”

Section: Discussionmentioning

confidence: 92%

“…20 Therefore, GDLBCL patients with high PD-L1 expression do not benefit from first-line treatment. 21 In literature reports, tumor cells that express PD-L1 have many mechanisms to escape T-cell immunity. 22 PD-1/PD-L1 pathway induces apoptosis of PD-1 + tumor-associated antigen-specific T cells, which is one of its important mechanisms.…”

Section: Discussionmentioning

confidence: 99%

<p>PD-L1 and miR-34a are Prognostic Factors for Primary Gastric Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP</p>

Wang

Shang

et al. 2020

CMAR

View full text Add to dashboard Cite

Introduction: Primary gastric diffuse large B-cell lymphoma (GDLBCL) is a heterogeneous disease in clinicopathological features and prognosis. Programmed death ligand-1 (PD-L1) and microRNA-34a (miR-34a) play crucial roles in GDLBCL progress. The purpose of this research is to explore the clinical significance of PD-L1 and miR-34a expression in GDLBCL. Patients and Methods: The expressions of PD-L1 and miR-34a were examined by IHC and qRT-PCR in 109 patients who were diagnosed with GDLBCL and were treated with rituximab plus cyclophosphamide, doxorubicin, prednisone vincristine and prednisone chemotherapy (R-CHOP) from January 2010 to December 2018. Results: PD-L1 level was significantly higher in tumor tissues than adjacent non-tumor tissues (60.5%, P<0.001), while the miR-34a level was just reversed (50.5%, P<0.001), which was negatively correlated (r=−0.524, P<0.001). Notably, PD-L1-positive and miR-34a-negative expressions were significantly correlated with the advanced Lugano stage of IIE-IV stage (P<0.001 and P<0.01), elevated serumal LDH levels (P<0.001 and P<0.05), B symptoms present (P<0.001 and P<0.001), non-GCB subtype (P<0.001 and P<0.001) and negative Bcl-2 expression (P<0.05 and P<0.001). PD-L1 high and miR-34a low expression groups had more patients with IPI scores of 2 or greater (P<0.001 and P<0.05) and poor R-IPI (P<0.01 and P<0.01). The complete response rate was upregulated in patients with negative PD-L1 and positive miR-34a expression after R-CHOP treatment. Discussion: PD-L1 expression and miR-34a expression were significantly associated with clinicopathological characteristics and survival prognosis; they may serve as novel prognostic markers in GDLBCL patients who were treated with R-CHOP. Immunotherapies targeting PD-L1 and miR-34a pathway may have therapeutic potential in GDLBCL.

show abstract

“…Data for the regulation of apoptotic susceptibility by PD-L1 derived from a limited number of studies in solid tumor cell lines [45][46][47]. We found that the intrinsic PD-L1 of tumor cells can regulate chemosensitivity, and knockout of PD-L1 can make human and mouse CRC cell lines resist the apoptosis induced by various cytotoxic drugs.…”

Section: Discussionmentioning

confidence: 95%

Loss of tumor intrinsic PD-L1 confers resistance to drug-induced apoptosis in human colon cancer

Feng¹,

Chen²,

He³

et al. 2021

neo

View full text Add to dashboard Cite

Colorectal cancer (CRC) with BRAF (V600E) is associated with microsatellite instability (MSI) that predicts response to immune checkpoint inhibitors. We demonstrated the interrogation of TCGA RNA-seq human datasets revealed that BRAFV600E tumors had significantly higher Programmed Death Ligand 1 (PD-L1) mRNA compared to non-mutated BRAF CRCs. Also, MSI-H tumors were evaluated as higher PD-L1 than MSS CRCs. Inhibition of MEK/ERK by cobimetinib or CDK inhibitor dinaciclib was shown to attenuate mutant BRAF-induced PD-L1 coincident with reduced c-JUN and YAP expression whose combined knockdown reduced PD-L1. Using TCGA datasets, PD-L1 mRNA expression in human colon cancers was significantly associated with YAP expression. The deletion of PD-L1 can reduce tumor cell growth shown by clonogenic assay. Analysis of the role of PD-L1 as a mediator of chemosensitivity was then performed. Knockout of PD-L1 was shown to attenuate the induction of DNA double-strand breaks (pH2AX) and caspase-3 cleavage by 5fluorouracil (5-FU) and paclitaxel compared to parental CRC cells. Results were confirmed in PD-L1 knockout MC38 murine CRC cells where re-expression of wild-type PD-L1 promoted DNA damage and apoptosis. We also performed the clonogenic assay and flow cytometry to prove that loss of PD-L1 attenuated DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1. Mechanistically, knockout of PD-L1 reduced chemosensitivity in association with reductions in p-AKT and in BH3-only proteins BIM and BIK, rather than STAT3 in CRC cells. However, STAT3 had a significant role in melanoma, which shows the heterogeneity of cancers. In summary, BRAFV600E can upregulate PD-L1 expression that was induced by c-jun and YAP to enhance chemotherapy-induced apoptosis. Together, we demonstrate a potential role for PD-L1 as a regulator of chemotherapy-induced apoptosis whose deletion or suppression confers chemoresistance. These findings expand the understanding of PD-L1 functions to include nonimmune mechanisms and suggest the potential use of PD-L1 as a biomarker of response to cytotoxic chemotherapy.

show abstract

Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

Cited by 17 publications

References 17 publications

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

<p>PD-L1 and miR-34a are Prognostic Factors for Primary Gastric Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP</p>

Loss of tumor intrinsic PD-L1 confers resistance to drug-induced apoptosis in human colon cancer

Contact Info

Product

Resources

About