Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma

Our plain-English summary of Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma, by S.J. Han, G. Reis, G. Kohanbash, et al (Journal of Neuro-oncology, 2016).

The study

• Authors: S.J. Han, G. Reis, G. Kohanbash, S. Shrivastav, S.T. Magill, A.M. Molinaro, M.W. McDermott, P.V. Theodosopoulos, M.K. Aghi, M.S. Berger, N.A. Butowski, I. Barani, J.J. Phillips, A. Perry, H. Okada
• Journal: Journal of Neuro-oncology
• Published: 2016;130(3):543-552
• Cited by: 102 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

In plain English

This study did not examine asbestos exposure. It studied meningioma, a tumor inside the skull; mesothelioma appears only as a comparison tissue for the protein mesothelin and as one cancer in a mesothelin-targeted treatment trial. The authors stained tissue from 96 meningiomas treated at the University of California, San Francisco, 1989 to 2012 (16 grade I, 62 grade II, 18 grade III). They stained for immune cells, PD-L1 (an immune-checkpoint molecule) and mesothelin, and counted cells with software. The average share of PD-L1-positive cells rose with grade: 0.91% (grade I), 2.63% (grade II), 8.84% (grade III). In multivariate analysis, PD-L1-positive cells that were not CD68-positive were linked to worse overall survival (hazard ratio 1.263 per 1% of cells, 95% confidence interval 1.067 to 1.496, p = 0.014). About a quarter of meningiomas had mesothelin levels near those measured in pancreatic carcinoma (13.8%) and mesothelioma (12.2%). The authors concluded that PD-L1 may play a biologic role in aggressive meningiomas. They noted that tissue cores may miss variation within tumors and that case selection may have introduced bias.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective laboratory study: immunohistochemistry staining of tissue microarrays from surgically treated meningiomas, linked to clinical follow-up and survival analysis
• Who was studied: 96 patients with meningioma (16 WHO grade I, 62 grade II, 18 grade III) treated at the University of California, San Francisco Medical Center between 1989 and 2012. The cohort was enriched for grade II and III cases.
• Exposure: No asbestos or fiber exposure was studied. The study measured immune cell markers (CD3, CD8, CD20, CD68), the immune-checkpoint molecule PD-L1, and mesothelin in meningioma tissue. Prior radiotherapy was examined as a treatment factor.
• Main results:
  • Context, not a finding: the authors studied mesothelin because it is the target of an early-phase trial of CAR T cells directed against mesothelin. That trial involves pancreatic carcinoma, ovarian carcinoma and malignant mesothelioma.
  • Across all meningiomas, the average percentage of PD-L1-positive cells was 0.91% in grade I, 2.63% in grade II and 8.84% in grade III tumors (ANOVA, p = 0.039).
  • Tumors that had undergone prior radiotherapy averaged 6.79% PD-L1-positive cells, compared with 2.50% in tumors that had not (p = 0.041).
  • PD-L1-positive cells that were CD68-negative were more numerous in higher grade tumors (p = 0.022) and in tumors with prior radiotherapy (p = 0.024).
  • Numbers of PD-L1-positive cells that were also CD68-positive (macrophages) did not differ significantly by tumor grade (p = 0.30).
  • The multivariate overall survival model accounted for age, Karnofsky performance status, grade and extent of resection.
  • In that model, a higher percentage of PD-L1-positive/CD68-negative cells was associated with worse overall survival (hazard ratio 1.263 per 1% of cells, p = 0.014).
  • The 95% confidence interval for that hazard ratio, as printed in Table 3, was 1.067 to 1.496.
  • When the same multivariate model used all PD-L1-positive cells instead, total PD-L1 was not predictive of overall survival (p = 0.179).
  • Infiltration by CD20-positive cells (B lymphocytes) was associated with better progression-free survival after accounting for grade and extent of resection (hazard ratio 0.966 per CD20-positive cell in core, p = 0.041).
  • In 36 samples, reported as 43.3%, CD68-positive macrophages were the main source of PD-L1 within the tumor tissue.
  • In comparison tissues stained the same way, mesothelin-positive cells made up 13.8% of pancreatic carcinoma and 12.2% of mesothelioma.
  • The 75th percentile of mesothelin staining in the meningiomas was 17%, meaning about a quarter of the meningiomas had mesothelin levels near those of pancreatic carcinoma and mesothelioma.
• The authors' conclusion: The authors concluded that PD-L1 on CD68-negative cells was independently linked to poor overall survival. They suggested that PD-L1 may play a significant biologic role in the aggressiveness of higher grade and radiotherapy-failed meningiomas. They added that checkpoint inhibitors or mesothelin-targeted approaches may have clinical utility.
• Limitations the authors state:
  • Tissue microarray cores may miss variation in the immune environment within a tumor.
  • Enriching the cohort for grade II/III tumors and for cases with enough tissue may have introduced selection bias.
  • The authors could not be certain that the CD68-negative, PD-L1-positive cells were all tumor cells.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Immunotherapy, Mesothelin, Immunohistochemistry, Overall Survival, Performance Status, Carcinoma, Malignant Mesothelioma.

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