Expression of V-set immunoregulatory receptor in malignant mesothelioma

Our plain-English summary of Expression of V-set immunoregulatory receptor in malignant mesothelioma, by Y.S. Chung, M. Kim, Y.J. Cha, et al (Modern Pathology, 2020).

The study

• Authors: Y.S. Chung, M. Kim, Y.J. Cha, K.A. Kim, H.S. Shim
• Journal: Modern Pathology
• Published: 2020;33(2):263-270
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is a highly lethal cancer. V-set immunoregulatory receptor (VSIR, also known as V-domain Ig suppressor T-cell activation, VISTA), a negative immune checkpoint regulator, was reported to be expressed in malignant mesothelioma; however, its detailed expression pattern and clinicopathological significance have not been elucidated. We examined the expression of VSIR and CD274 and CD8+ tumor-infiltrating lymphocytes in a total of 124 samples from 66 patients with malignant mesothelioma and analyzed the clinicopathological characteristics and their relationship with the immunohistochemical findings. A total of 553 non-small cell lung carcinomas were also evaluated for VSIR expression. VSIR expression was higher in epithelioid type mesothelioma (p < 0.001), whereas CD274 expression was higher in sarcomatoid type (p < 0.001). CD8+ tumor-infiltrating lymphocytes were more abundant in sarcomatoid mesotheliomas (p < 0.001), VSIR-low tumors (p = 0.045), and CD274-high tumors (p < 0.001). VSIR and CD274 were differentially expressed in each histological component of the biphasic type. VSIR expression was associated with favorable survival (p = 0.008). Two patients with VSIR-high tumors had received pembrolizumab; however, they showed progressive disease. No VSIR expression was observed in tumor cells of non-small cell lung carcinomas. In conclusion, VSIR expression may define a unique class of mesothelioma, characterized by predominantly epithelioid type and favorable prognosis. VSIR expression may be used as an immunohistochemical diagnostic marker for epithelioid mesothelioma. CD274 expression was associated with sarcomatoid mesothelioma and high infiltration of CD8+ lymphocytes. Because VSIR is a negative immune regulator and expressed in malignant mesothelioma, further study is warranted to investigate the therapeutic significance of VSIR blockade in this deadly cancer.

In plain English

This retrospective study examined archived tissue from 66 patients with malignant mesothelioma who presented at one institution in Seoul, Korea, between 2001 and 2017. The 124 samples came from 50 pleural and 16 peritoneal cases; only three patients had a recorded history of asbestos exposure. The samples were stained for VSIR (VISTA), a protein that dampens immune responses, and for CD274 (PD-L1) and CD8+ immune cells. VSIR was more common in epithelioid tumors: at a 5% cutoff, 94% of epithelioid samples were positive, against 55% of sarcomatoid samples. CD274 and CD8+ cells were higher in sarcomatoid tumors. VSIR expression was linked to longer overall survival (p = 0.008). After adjustment for age, sex, stage, subtype and site, VSIR expression below 5% carried a hazard ratio of 3.019 (95% confidence interval 1.25 to 7.72). Two patients with VSIR-high tumors who received pembrolizumab had progressive disease. VSIR was not definitely found in tumor cells of 553 non-small cell lung carcinomas. The authors concluded that VSIR may define a distinct, mostly epithelioid group with a better prognosis and could be a diagnostic marker for epithelioid mesothelioma. Because VSIR also stains benign mesothelial cells, they noted it cannot separate benign mesothelial proliferation from epithelioid mesothelioma. The authors listed the small cohort and the few asbestos-exposed patients as limitations.

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 pathology study of archived tumor samples (immunohistochemistry) with survival analysis; lung cancer tissue microarrays used for comparison
• Who was studied: 66 patients with malignant mesothelioma (44 men, 22 women, aged 19 to 85) who presented at the authors' institution (Yonsei University, Seoul, Korea) between 2001 and 2017, with 124 samples in total. By type: 50 epithelioid, 11 sarcomatoid and 5 biphasic. By site: 50 pleural and 16 peritoneal. A separate set of 553 non-small cell lung carcinomas (404 adenocarcinomas, 132 squamous cell carcinomas, 17 large cell carcinomas) was also examined.
• Exposure: The study measured tumor expression of VSIR (VISTA) and CD274 (PD-L1), and counts of CD8+ tumor-infiltrating lymphocytes. It did not study asbestos exposure as such: only 3 of the 66 patients had a history of asbestos exposure, and no fiber types are given.
• Main results:
  • VSIR expression was higher in epithelioid than in sarcomatoid mesothelioma (p less than 0.001). At cutoffs of 5% and 50% of tumor cells, 94% and 78% of epithelioid samples were VSIR-positive, compared with 55% and 0% of sarcomatoid samples.
  • VSIR was expressed in both malignant and benign mesothelial cells. CD274 was not present in benign mesothelial cells.
  • The authors stated that, because VSIR is also expressed in benign mesothelial cells, it cannot be used to differentiate benign mesothelial proliferation from epithelioid mesothelioma.
  • CD274 expression was higher in sarcomatoid than in epithelioid mesothelioma (p less than 0.001). At 5% and 50% cutoffs, 18% and 8% of epithelioid samples were positive, compared with 55% and 46% of sarcomatoid samples.
  • CD8+ tumor-infiltrating lymphocytes were more abundant in sarcomatoid than in epithelioid tumors (p less than 0.001), in VSIR-low tumors (p = 0.045) and in CD274-high tumors (p less than 0.001).
  • Mean follow-up was 21 months. Overall survival did not differ significantly by histological type (p = 0.590), CD274 expression (p = 0.783) or CD8+ lymphocytes (p = 0.522). VSIR expression (cutoff 5%) was a favorable prognostic factor in all patients (p = 0.008) and in the epithelioid subgroup (p less than 0.001).
  • In multivariate analysis including age, sex, stage, subtype and site, low VSIR expression (less than 5%) was an independent poor prognostic factor (hazard ratio 3.019, 95% confidence interval 1.25 to 7.72, p = 0.014).
  • Two patients with epithelioid mesothelioma received pembrolizumab and showed progressive disease. VSIR was expressed in 70% and 100% of their tumor cells respectively, and neither tumor expressed CD274.
  • VSIR was not definitely expressed in tumor cells of the 553 non-small cell lung carcinomas. Only two cases showed patchy cytoplasmic staining in less than 5% of tumor cells.
• The authors' conclusion: The authors concluded that VSIR expression may define a unique class of mesothelioma, mainly epithelioid type with a favorable prognosis, and that it can be used as a diagnostic marker for epithelioid mesothelioma. They also concluded that CD274 expression was associated with sarcomatoid mesothelioma and high CD8+ lymphocyte infiltration, and that further study of VSIR blockade as a treatment is warranted.
• Limitations the authors state:
  • Only three patients had a history of asbestos exposure, so the authors could not obtain statistically meaningful data on asbestos exposure.
  • The cohort was small. Because of this, no survival difference was seen for previously known prognostic factors such as subtype.
  • Only two patients received a programmed cell death 1 inhibitor, which limited any assessment of the link between immune markers and response to immunotherapy.
  • Tissue microarrays may not fully reflect uneven VSIR expression in lung cancer.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Tumor-Infiltrating Lymphocytes, Carcinoma, Epithelioid, Mesothelioma, Sarcomatoid, Biphasic Mesothelioma, Pembrolizumab (Keytruda).

Related studies

• V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma — S. Muller, W. Victoria Lai, et al. (2020)
• Expression status of PD-L1 and B7-H3 in mesothelioma — E. Matsumura, K. Kajino, et al. (2020)
• Expression and regulation of B7-H3 immunoregulatory receptor, in human mesothelial and mesothelioma cells: immunotherapeutic implications — L. Calabrò, L. Sigalotti, et al. (2011)
• Tumour infiltrating lymphocytes and PD-L1 expression as potential predictors of outcome in patients with malignant pleural mesothelioma — N. Sobhani, G. Roviello, et al. (2019)
• Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas — C. Combaz-Lair, F. Galateau-Sallé, et al. (2016)
• Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma — S. Inaguma, J. Lasota, et al. (2018)

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