Programmed Cell Death Protein 1/Programmed Cell Death Ligand-1 Axis activates Intracellular ERK Signaling in Tumor Cells to Mediate Poor Prognosis in T-cell Lymphoma

The programmed cell death 1/programmed cell death ligands (PD-1/PD-Ls) axis is a potential immune escape mechanism of cancers. However, data on the PD-1/PD-Ls pathway in EBV-associated extranodal natural killer/T cell lymphoma (ENKTL) and its clinical implication are limited. Herein, we characterized PD-1/PD-L expression and its prognosis relevance in 49 ENKTL patients in Thailand. PD-L1 was expressed frequently on both lymphoma cells (61.2%) and stroma (77.5%), whereas PD-L2 expression was more common on lymphoma (63.2%) than stromal cells. PD-1 was positive in 20.5% of stroma, but undetectable on lymphoma cells. There was no association between baseline clinical characteristics and the expression PD-1/PD-Ls. The survival of patients with PD-Ls on tumor cells was poor. For PD-L1-positive versus negative cases, the 2-year event-free survival (EFS) was 42.2 versus 71.8% (p = 0.03) and 2-year overall survival (OS) was 45.4 versus 78.9% (p = 0.02), respectively. Comparing between patients with PD-L2-positive and PD-L2-negative lymphoma, the 2-year EFS was 37.1 versus 82.4% (p = 0.02) and 2-year OS was 45.2 versus 82.4% (p = 0.03), respectively. Neither PD-1 nor PD-Ls expression in the stroma predicted outcomes. In conclusion, PD-Ls were frequently expressed on ENKTL cells and associated with inferior outcomes. Therefore, PD-Ls are potential prognostic biomarkers and the roles of immune checkpoint blockade therapy in ENKTL deserve further investigation.

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Expression of programmed cell death ligand 1 (PD-L1) in advanced stage EBV-associated extranodal NK/T cell lymphoma is associated with better prognosis

Virchows Archiv ◽

10.1007/s00428-016-2011-0 ◽

2016 ◽

Vol 469 (5) ◽

pp. 581-590 ◽

Cited By ~ 29

Author(s):

Wook Youn Kim ◽

Ho Young Jung ◽

Soo Jeong Nam ◽

Tae Min Kim ◽

Dae Seog Heo ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Advanced Stage ◽

Nk T Cell

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Corrigendum to “Alkylphosphocholines and curcumin induce programmed cell death in cutaneous T-cell lymphoma cell lines” [Leukemia Res. 38 (2014) 49–56]

Leukemia Research ◽

10.1016/j.leukres.2014.02.004 ◽

2014 ◽

Vol 38 (4) ◽

pp. 516

Author(s):

Deyan Y. Yosifov ◽

Kaloyan A. Kaloyanov ◽

Margarita L. Guenova ◽

Kamelia Prisadashka ◽

Maria B. Balabanova ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cell Lines ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Lymphoma Cell ◽

Cutaneous T Cell Lymphoma

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Bortezomib Restores Defective Apoptosis by Upregulation of Noxa in Enteropathy-Associated T-Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2722.2722 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2722-2722

Author(s):

Laura R de Baaij ◽

Marijn Radersma ◽

Jolanda MW van de Water ◽

Kim BJ Groot ◽

Nathalie J Hijmering ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Cells ◽

Cell Lymphoma ◽

Chemotherapy Resistance ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Caspase 9 ◽

Apoptosis Pathway ◽

Induction Of Apoptosis

Abstract Abstract 2722 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. Clinical outcome of patients with EATL is very poor, due to chemotherapy-resistance and high relapse rates. Therefore, new therapeutic options for EATL are urgently needed. Studies in other types of lymphoma have shown that inhibition of apoptosis may cause chemotherapy-resistance and that restoration of defective apoptosis can induce cell death in these lymphomas. Preliminary data in EATL samples have demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in EATL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In the present study, we evaluated if apoptosis is inhibited in EATL cells and if Bortezomib can restore apoptosis in EATL cells. Laser-capture microdissection was applied to 16 fresh frozen EATL samples to obtain purified tumor cells for RNA isolation. Intraepithelial lymphocytes (IEL) of healthy controls were obtained from fresh duodenal biopsies and isolated by cell sorting. RT-MLPA analysis revealed that the pro-apoptotic BH3-only gene Noxa was significantly downregulated in most EATL samples compared to healthy donor IEL. Induction with etoposide resulted in caspase-9 mediated apoptosis in EATL cells with relatively high Noxa expression, whereas in EATL cells with low Noxa expression no apoptosis was induced, suggesting an inhibition in the intrinsic apoptosis pathway. Treatment with Bortezomib resulted in induction of apoptosis in EATL cells. The lethal dose (LD50) varied between 7.5 nM and 15 nM. Bortezomib induced cell death in EATL cells was caspase-9 mediated. mRNA and protein expression analysis showed upregulation of Noxa after incubation with bortezomib. In conclusion, our study showed that bortezomib induces apoptosis by upregulation of Noxa in EATL cells. Bortezomib therefore may be a potential drug in the treatment of patients with EATL. Disclosures: No relevant conflicts of interest to declare.

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Expression of Programmed Cell Death 1 and Programmed Cell Death Ligand 1 in Extranodal NK/T-Cell Lymphoma, Nasal Type

Blood ◽

10.1182/blood.v126.23.1461.1461 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1461-1461

Author(s):

Jae-Cheol Jo ◽

Yunsuk Choi ◽

Hee Jeong Cha ◽

Eun Hee Lee ◽

Eun Kyoung Kang ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Research Funding ◽

Cell Lymphoma ◽

Prognostic Index ◽

T Cell Lymphoma ◽

Nasal Type ◽

Programmed Cell Death 1 ◽

Nk T Cell

Abstract Background Programmed cell death ligand 1 (PD-L1) is expressed on extranodal NK/T-cell lymphoma, nasal type (ENKL) tumor cells. The programmed cell death 1 (PD-1) and PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in ENKL. The aim of this study was to investigate the expression of PD-1 and PD-L1 and to determine the clinicopathological impact of PD-1 and PD-L1 positivity in ENKL. Methods We performed PD-1 and PD-L1 immunostaining in 79 ENKL biopsy samples and retrospectively analyzed medical records of all 79 patients from 4 tertiary referral hospitals. The demographic features, performance status, stage, LDH, primary sites, nodal sites, hemoglobin, white blood cell, platelet, creatinine, international prognostic index (IPI), and prognostic index for T-cell lymphoma (PIT) were recorded. Results The expression rates of PD-1-positive and PD-L1-positive ENKL were 7.6% and 88.6%, respectively (Figure 1A & 1B). PD-L1-negative ENKL (n=9) was significantly associated with high intermediate or high risk IPI (n=7, P=0.002) and group 3 or 4 PIT (n=6, P=0.043). Patients with PD-1-positive ENKL (n=6) had a trend toward better overall survival (OS) compared with that in patients with PD-1-negative ENKL (P = 0.090, Figure 2A). In contrast, there was no significant difference in OS between PD-L1-positive and -negative ENLK (P = 0.428, Figure 2B). Conclusions This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKL. PD-1 expression rate is very low, and PD-L1 negativity is associated with poor risk groups of IPI and PIT in ENKL Disclosures Kim: Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Celgene: Research Funding; Novartis: Research Funding.

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