Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

Li, Linyu; Zhang, Tingting; Zheng, Shu; Zhang, Xuhan; Liu, Jing; Liu, Xianming; Qiu, Lihua; Zheng, Qian; Zhou, Shunhua; Feng, Lixia; Hu, Ge; Meng, Bin; Zhai, Qiong-Li; Ren, Xiubao; Fu, Kai; Li, Lanfang; Wang, Ping; Zhang, Huilai

doi:10.1002/ijc.32144

Cited by 28 publications

(26 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiplexed immunofluorescence staining was performed as described in our previous study [ 15 ], to visualise the expression of Tim-3, CD8, and PAX-5. Here, PAX-5 was used to localise the tumor cells.…”

Section: Methodsmentioning

confidence: 99%

Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma

Zhang

Ren

Zheng

et al. 2020

Journal of Immunology Research

Self Cite

View full text Add to dashboard Cite

Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3+ TILs) exhibited poor outcomes than those with Tim-3- TILs ( p = 0.041 ). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and found that patients with exhausted Tim-3+ CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3- CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; p = 0.034 ). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.

show abstract

Section: Methodsmentioning

confidence: 99%

Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma

Zhang

Ren

Zheng

et al. 2020

Journal of Immunology Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…In order to precisely detect the PD-L1 and PAX-5 (paired box 5) expression, multiplexed immunofluorescence staining was performed in twenty-nine matched formalin-fixed paraffin-embedded (FFPE) tissues from patients before treatment according to the Opal immunostaining protocol, as described in our previous study 35 . Each FFPE tumor section needed two sequential rounds of staining.…”

Section: Methodsmentioning

confidence: 99%

Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients

Fei¹,

Yu²,

Li³

et al. 2020

J. Cancer

Self Cite

View full text Add to dashboard Cite

Purpose: Diffuse large B cell lymphoma (DLBCL) is one of the most common B cell lymphomas, which displays heterogeneous pathologies. Programmed cell death 1/ programmed cell death ligand 1 (PD-1/PD-L1) plays an essential role in immunosuppression in multiple malignancies. Signal transducer and activator of transcription 3 (STAT3)-positive patients also have an independently inferior clinical outcome. However, there are no reports on the effect of plasma soluble PD-L1 (sPD-L1) combined with plasma STAT3 on the prognosis of DLBCL. In this study, we investigate the relationships between plasma sPD-L1 combined with STAT3 and clinical prognosis of DLBCL. Methods: Levels of plasma sPD-L1 and STAT3 were quantified using ELISA in eighty-seven DLBCL patients. Multiplexed immunofluorescence staining was performed to visualize the expression of PD-L1 in twenty-nine matched FFPE specimens from all patients. Results: The survival analysis revealed that the progression-free survival (PFS) and overall survival (OS) in high sPD-L1 level group were poorer than that in low sPD-L1 level group (PFS, P < 0.001; OS, P < 0.001). Similarly, the PFS and OS in high STAT3 level group were also poorer than that in low STAT3 level group. Multivariate cox regression analysis showed that both high sPD-L1 and high STAT3 levels were the independent prognostic factors negatively affecting survival. In addition, patients with DLBCL having high levels of both sPD-L1 and STAT3 had a worse outcome than those patients having any one high or low levels of both ( P < 0.001). Conclusions: We therefore revealed that high levels of plasma sPD-L1 and STAT3 are associated with inferior outcome for DLBCL patients, suggesting that combined measurement of their levels in plasma may be a promising prognostic strategy for DLBCL patients.

show abstract

“…During recent years, several T-cell-based adoptive immunotherapies have emerged to stimulate and redirect T-cell functions against tumors (45), and the CD8 + T-TIL status was associated with the clinical outcome of DLBCL (46). Numerous innovative T-cell-based immunotherapy approaches have shown promising results in relapsed or refractory DLBCL patients, leading to a number of ongoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%

MiRNA-340-5p mediates the functional and infiltrative promotion of tumor-infiltrating CD8+ T lymphocytes in human diffuse large B cell lymphoma

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: CD8+ tumor-infiltrating T lymphocytes (T-TILs) in the tumor microenvironment (TME) play an important role in tumor development, and miRNAs regulate tumor cell interactions with the microenvironment. T-TIL-based tumor immunotherapy provides a promising treatment strategy in diffuse large B-cell lymphoma (DLBCL). MiRNAs tend to be attractive targets for novel antitumor interventions. Methods: Weighted gene coexpression network analysis (WGCNA), CIBERSORT analysis and Cox regression analysis were used to identify CD8+ T-TIL-related miRNAs. RT-PCR, western blotting, immunohistochemistry (IHC), in situ hybridization (ISH), luciferase reporter assay, coimmunoprecipitation and ubiquitination analyses were used to detect miRNA, mRNA and protein expression and their combination. The viability and function of CD8+ T cells after stimulation were evaluated by enzyme-linked immunosorbent assay (ELISA), cytotoxicity assay, functional avidity assessment, flow cytometry and Cell Counting Kit-8 (CCK-8) assay. DLBCL cell lines, primary cells and a murine xenograft model established with A20 cell injection were used as in vitro and in vivo experimental models. Results: MiR-340-5p was positively correlated with CD8+ T-TILs in DLBCL patients, and KMT5A was a direct target gene of miR-340-5p. CD8+ T-cell function was significantly enhanced by miR-340-5p mimics both in vitro and in vivo, which was reversed by KMT5A overexpression. We demonstrated that COP1/CD73 was involved in the downstream mechanism of the miR-340-5p/KMT5A axis involving ubiquitination. In vivo, we validated an improved CD8+ T-TIL infiltration rate and tumor suppression with miR-340-5p treatment. Furthermore, miR-340-5p directly regulated the biological activity of DLBCL cells without CD8+ T-cell participation. Conclusions: MiR-340-5p promoted CD8+ T-TIL infiltration and antitumor function by regulating KMT5A and COP1 and further activating CD73 ubiquitination. MiR-340-5p is potentially a novel target for DLBCL immunotherapy.

show abstract

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

Cited by 28 publications

References 29 publications

Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma

Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma

Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients

MiRNA-340-5p mediates the functional and infiltrative promotion of tumor-infiltrating CD8+ T lymphocytes in human diffuse large B cell lymphoma

Contact Info

Product

Resources

About