Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

Kiyasu, Junichi; Miyoshi, Hiroaki; Hirata, Akie; Arakawa, Fumiko; Ichikawa, Ayako; Niino, Daisuke; Sugita, Yasuo; Yufu, Yuji; Choi, Ilseung; Abe, Yasunobu; Uike, Naokuni; Nagafuji, Koji; Okamura, Takashi; Akashi, Koichi; Takayanagi, Ryoichi; Shiratsuchi, Motoaki; Ohshima, Koichi

doi:10.1182/blood-2015-02-629600

Cited by 399 publications

(523 citation statements)

References 38 publications

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“…This has already been reported in several cancers, 15,58,[62][63][64][65][66] although a favorable prognostic value has been reported in other cancers. 50,55,59,[67][68][69] For comparison and to our knowledge, only four studies-three publications 8,15,42 and one meeting presentation 70 -have described PDL1 expression and clinicopathological correlations in STS.…”

Section: Discussionmentioning

confidence: 83%

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

et al. 2017

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Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery. PDL1 expression was heterogeneous across the samples. PDL1-high samples (41%) were more frequently leiomyosarcomas and liposarcomas, and showed more frequently a complex genetic profile and a high-risk CINSARC signature. No correlation existed with other clinicopathological features such as tumor site, depth, and pathological tumor grade and size. In multivariate prognostic analysis, the PDL1-high class was associated with shorter MFS, independently of the pathological type and the CINSARC signature. Analysis of correlations with biological factors suggested the existence in tumors of the PDL1-high class of a strong and efficient cytotoxic T-cell response, however associated with some degree of T-cell exhaustion and negative regulation. In conclusion, we show that PDL1 expression refines the prediction of metastatic relapse in operated localized STS, and that PD1/PDL1 blockade holds potential to improve patient survival by reactivating inhibited T cells to increase the antitumor immune in PDL1-high tumors.

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Section: Discussionmentioning

confidence: 83%

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

et al. 2017

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“…A retrospective study assessed the association between PD-L1 expression level and overall survival rates in DLBCL, demonstrating that patients with PD-L1 + DLBCL exhibited poorer overall survival rates compared with patients with PD-L1 -DLBCL (17). This suggests that the PD-1/PD-L1 pathway may be a prospective immunotherapy target in this distinct DLBCL subgroup.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Abstract.Interaction between the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) contributes to tumor cell resistance to chemotherapeutic agents. PD-L1 is expressed in the cells of diffuse large B-cell lymphoma (DLBCL), one common type of malignant non-Hodgkin lymphomas. However, little is known about how the PD-1/PD-L1 pathway functions in the pathogenesis of DLBCL. Therefore, the present study investigated whether and how the PD-1/PD-L1 axis is involved in regulating the sensitivity of CRL2631, a DLBCL cell line, to the CHOP (Cyclophosphamide, Hydroxydaunorubicin/adriamycin, Oncovin/vincristine and Prednisone) chemotherapeutic regimen. CHOP treatment significantly decreased cell survival rate and increased apoptosis in CRL2631 cells. The application of recombinant human PD-1 (rPD-1) significantly decreased the cytotoxic effects of the CHOP regimen in CRL2631 cells, but not in the CRL2631 cells with PD-L1 deficiency. In the CRL2631 cells, rPD-1 enhanced the activity of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt1) pathway. However, the activity level of the PI3K/Akt1 pathway was decreased in CHOP-treated CRL2631 cells. The selective PI3K inhibitor BKM120 significantly increased CHOP-induced apoptosis, but this effect was abolished by rPD-1 and aggravated by PD-L1 knockdown. In CHOP-treated PD-L1 knockdown cells, the increased apoptosis was markedly inhibited by the overexpression of constitutively active Akt1. Overall, the results demonstrate that the over-activated PD-1/PD-L1 axis is associated with chemotherapeutic resistance of DLBCL cells to the CHOP regimen, potentially through a PI3K-dependent mechanism.

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“…Although frequency of PD-L1 expression in DLBCL have varied among several studies, [6][7][8][9] no study focusing on PD-L1 expression in IVLBCL has been reported. Four et al 12 recently reported a higher rate of PD-L1 expression (clone SP142) on tumor cells in PCNS-DLBCL than in S-DLBCL (58% and 37%, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…In parallel, studies have focused on analyzing of the PD1/ PD-L1 axis for prognostic relevance and prediction of treatment response. 4,[6][7][8][9][10] With regards to lymphoid malignancies, tumor cell PD-L1 expression is frequently reported in classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma, and Epstein-Barr virus (EBV)-associated lymphomas, including EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) type, and extranodal NK/T-cell lymphoma, nasal type 11 according to the WHO 2017 classification. 1 Moreover, a recent report describes a higher incidence of neoplastic PD-L1 overexpression in primary DLBCL of the CNS (PCNS-DLBCL) compared to systemic ordinal cases.…”

Section: Introductionmentioning

confidence: 99%

Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression

Sakakibara

Inagaki

Imaoka

et al. 2018

J Clin Exp Hematopathol

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Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly. Random skin biopsy for IVLBCL diagnosis yielded negative results. The patient experienced a rapidly deteriorating clinical course with no treatment, and died from the disease after 3 months of hospitalization. Post-mortem examination revealed systemic intravascular plugging of lymphoma cells, without mass lesions in the central nervous system or in visceral organs such as the lungs, liver, pituitary gland, ovaries, and uterus. The tumor cells were positive for CD10, CD20, BCL2, BCL6, and MUM1, but not other lineage-specific markers. Notably, the tumor cells showed strong PD-L1 expression. Our case was diagnosed as IVLBCL with neoplastic PD-L1 expression. These findings suggest that PD-L1 is associated with immune evasion of IVLBCL and may play a role in the pathogenesis and peculiar biological behavior of this unique disease. Additionally, PD-L1 may represent a possible therapeutic target for immune check-point inhibitors.

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Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

Cited by 399 publications

References 38 publications

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

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

Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression

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