HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma

Zhou, Qiang; Li, Kai Wen; Chen, Zhanghua; He, Hai Xia; Peng, Sheng Meng; Peng, Shi Rong; Wang, Qiong; Li, Ze An; Tao, Yi; Cai, Wenli; Liu, Ran Yi; Huang, Hai

doi:10.1136/jitc-2019-000157

Cited by 69 publications

(71 citation statements)

References 32 publications

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“…According to Teng's theory, it may be much more rational to classify by inflammatory cells via the combination PD-L1 and CMTM6 or in combination with other CMTM family members in HCC [34]. Consistent with previous study, our results demonstrated that in inflammatory cell-positive groups, CMTM6/ PD-L1 coexpression displayed significant prognostic value for DFS and OS in MTM subtype [35]. These results suggested that both CMTM6 and PD-L1 perform immunosuppressive functions that partly depend on suppression of the inflammatory cell function.…”

Section: Discussionsupporting

confidence: 89%

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Liu

Zhang

Chao

et al. 2020

Cancer Immunol Immunother

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The "macrotrabecular-massive" (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients.

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Section: Discussionsupporting

confidence: 89%

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Liu

Zhang

Chao

et al. 2020

Cancer Immunol Immunother

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“…CD8+ or Foxp3+ TILs were calculated in the same manner as described in the previous study. 16 In brief, the average of five independent high-power fields (400×), which represented the densest lymphocytic infiltrates, was used to reflect the extent of T cell infiltration.…”

Section: Methodsmentioning

confidence: 99%

VISTA and PD-L1 synergistically predict poor prognosis in patients with extranodal natural killer/T-cell lymphoma

Gao

et al. 2021

OncoImmunology

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Although PD-1/PD-L1 blockade therapy confers salutary effects across cancer types, their efficacy in Extranodal Natural killer/T-cell lymphoma (ENKTCL) patients is limited and unpredictable. Here, we comprehensively evaluated the expression profile of a panel of immune-regulatory makers to identify novel prognostic biomarkers and/or therapeutic targets for this malignancy. Using immunohistochemistry and multiplex immunofluorescence, we found that the expression of VISTA (88.1%) was predominantly in CD68+ macrophages and much higher than PD-L1 expression (68.7%) in ENKTCL. B7-H4 and HHLA2 proteins were not detected in ENKTCL. B7-H3 was expressed in minority of ENKTCL patients (13.7%) and mainly colocalized with CD31. A close correlation was detected between VISTA and PD-L1, but they were not co-expressed in the same cells. High expressions of VISTA or PD-L1 were significantly associated with detrimental clinicopathological characteristics, dismal prognosis, and high density of CD8+ TILs, and high VISTA expression was also significantly associated with high density of Foxp3+ TILs. VISTA combined with PD-L1 was an independent prognostic factor for PFS and OS. Moreover, the patients with high VISTA showed a poor response to PD-1 blockades in ENKTCL. In conclusion, these findings provide a rationale for VISTA as an ideal immunotherapeutic target next to PD-L1 for ENKTCL.

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“…Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), also known as B7H7 or B7-H5, is a newly discovered member of the B7 family. [ 13 ] HHLA2 effectively suppresses the activity of CD4+ and CD8+ T cells and reduces the expression of T cell cytokines, such as interferon-γ, tumor necrosis factor-α, interleukin (IL)-5, IL-10, IL-13, IL-17α and IL-22. [ 14 ] In addition, HHLA2 is an inducer of the inflammatory response of antigen-presenting cells.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of HHLA2 expression in solid tumors

Zhang

et al. 2021

Medicine

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Background: Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a newly discovered member of the B7 family, is overexpressed in numerous tumors. However, the prognostic impact of HHLA2 in human cancers remains controversial. Thus, we performed this meta-analysis to explore the prognostic value of HHLA2 in Chinese patients with solid tumors.Methods: PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, and WanFang databases were systematically searched for eligible studies that evaluated the impact of HHLA2 on overall survival (OS) in patients with cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined to evaluate the association between HHLA2 expression and OS in solid tumors. Odds ratios (ORs) and 95% CIs were pooled to assess the correlation between HHLA2 expression and clinicopathological characteristics in solid tumors.Results: A total of 12 studies, including 15 cohorts and 1747 patients, were included in this meta-analysis. We found that high HHLA2 expression was significantly associated with shorter OS (HR = 1.65, 95% CI: 1.12-2.43). Subgroup analysis by cancer type demonstrated that high HHLA2 expression was associated with poor OS in patients with clear cell renal cell carcinoma (HR = 3.42, 95% CI: 2.39-4.91), gastric cancer (HR = 2.03, 95% CI: 1.31-3.16), intrahepatic cholangiocarcinoma (HR = 1.77, 95% CI: 1.24-2.53), lung cancer (HR = 2.14, 95% CI: 1.33-3.44) and other cancer types (HR = 2.08, 95% CI: 1.34-3.24), but not in patients with epithelial ovarian cancer (HR = 0.52, 95% CI: 0.08-3.56). Nevertheless, high HHLA2 expression was associated with better OS in patients with pancreatic ductal adenocarcinoma (HR = 0.45, 95% CI: 0.32-0.64). Furthermore, high HHLA2 expression was associated with old age (OR = 1.30, 95% CI: 1.03-1.63), lymph node metastasis (OR = 1.99, 95% CI: 1.41-2.81), and vascular invasion (OR = 1.69, 95% CI: 1.18-2.42).Conclusions: HHLA2 may serve as a potential prognostic biomarker for solid tumors in Chinese population, by predict the prognosis of cancer patients based on their tumor types.Abbreviations: ccRCC = clear cell renal cell carcinoma, CIs = confidence intervals, CRC = colorectal cancer, CTLA-4 = cytotoxic T lymphocyte-associated antigen-4, EOC = epithelial ovarian cancer, GC = gastric cancer, HHLA2 = Human endogenous retrovirus-H long terminal repeat-associating protein 2, HR = Hazard ratio, ICC = intrahepatic cholangiocarcinoma, IHC = immunohistochemistey, IL = interleukin, LC = lung cancer, NOS = Newcastle-Ottawa Scale, ORs = odds ratios, OS = overall survival, OSCC = oral squamous cell carcinoma, PD-1 = programmed cell death protein 1, PDAC = pancreatic ductal adenocarcinoma,.

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HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma

Cited by 69 publications

References 32 publications

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

VISTA and PD-L1 synergistically predict poor prognosis in patients with extranodal natural killer/T-cell lymphoma

Prognostic value of HHLA2 expression in solid tumors

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