V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma

Our plain-English summary of V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma, by S. Muller, W. Victoria Lai, P.S. Adusumilli, et al (Modern Pathology, 2020).

The study

• Authors: S. Muller, W. Victoria Lai, P.S. Adusumilli, P. Desmeules, D. Frosina, A. Jungbluth, A. Ni, T. Eguchi, W.D. Travis, M. Ladanyi, M.G. Zauderer, J.L. Sauter
• Journal: Modern Pathology
• Published: 2020;33(2):303-311
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

V-domain Ig-containing suppressor of T-cell activation (VISTA) is an immune checkpoint gene that inhibits anti-tumor immune responses. Since most malignant pleural mesotheliomas do not respond to anti-programmed cell death(-ligand)1 (PD-(L)1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) therapy and given the recent finding of The Cancer Genome Atlas Study that pleural mesothelioma displays the highest expression of VISTA among all cancers studied, we examined VISTA expression in a large pleural mesothelioma cohort. VISTA and PD-L1 immunohistochemistry were performed on tissue microarray of immunotherapy-naive pleural mesotheliomas (254 epithelioid, 24 biphasic and 41 sarcomatoid) and ten whole-tissue sections of benign pleura (VISTA only). Percentages of tumor and inflammatory cells with positive staining were assessed. Optimal prognostic cutoff percentages were determined using maximally selected rank statistics. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. All benign mesothelium expressed VISTA. Eighty-five percent of 319 and 38% of 304 mesotheliomas expressed VISTA and PD-L1 (88% and 33% of epithelioid, 90% and 43% of biphasic, and 42% and 75% of sarcomatoid), respectively. Median VISTA score was significantly higher in epithelioid (50%) (vs. biphasic [20%] and sarcomatoid [0]) (p < 0.001), while median PD-L1 score was significantly higher in sarcomatoid tumors (20%) (vs. biphasic and epithelioid [both 0%]) (p < 0.001). VISTA and PD-L1 were expressed in inflammatory cells in 94% (n = 317) and 24% (n = 303) of mesothelioma, respectively. Optimal prognostic cutoffs for VISTA and PD-L1 were 40% and 30%, respectively. On multivariable analysis, VISTA and PD-L1 expression in mesothelioma were associated with better and worse overall survival (p = 0.001 and p = 0.002), respectively, independent of histology. In a large cohort of mesothelioma, we report frequent expression of VISTA and infrequent expression of PD-L1 with favorable and unfavorable survival correlations, respectively. These findings may explain poor responses to anti-PD-(L)1 immunotherapy and suggest VISTA as a potential novel target in pleural mesothelioma.

In plain English

This laboratory study from Memorial Sloan Kettering Cancer Center looked at stored tumor tissue from 319 patients with malignant pleural mesothelioma. The samples dated from 1989 to 2010; no patient had received immunotherapy. It also examined ten benign (non-cancerous) mesothelium samples. Using immunohistochemistry staining, the authors measured two immune checkpoint proteins, VISTA and PD-L1. All benign samples stained for VISTA. VISTA was found in tumor cells in 270 (85%) of 319 mesotheliomas: 88% of epithelioid, 90% of biphasic and 42% of sarcomatoid. PD-L1 was found in 115 (38%) of 304, most often in sarcomatoid tumors (75% of 24). After adjustment for histology, stage, age and gender, each 10-percentage-point rise in the share of tumor cells staining for VISTA was associated with better overall survival (hazard ratio 0.94, 95% CI 0.91 to 0.98). The same rise in the share of tumor cells staining for PD-L1 was associated with worse survival (hazard ratio 1.1, 95% CI 1.0 to 1.1). The authors concluded that VISTA should be explored as a treatment target. They named variation within tumors and small tissue cores 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 laboratory (immunohistochemistry) study of archived tumor tissue on tissue microarrays, with survival analysis
• Who was studied: 319 immunotherapy-naive malignant pleural mesotheliomas from the Memorial Sloan Kettering Cancer Center archives, tumor samples procured 1989 to 2010. Table 1 lists 254 epithelioid, 41 biphasic and 24 sarcomatoid; 237 male and 82 female; median age 64. The study also included ten whole-tissue sections of benign mesothelium.
• Main results:
  • All ten benign mesothelium samples stained positive for VISTA.
  • VISTA was found in tumor cells in 270 (85%) of 319 mesotheliomas: epithelioid 223 (88%) of 254, biphasic 37 (90%) of 41, sarcomatoid 10 (42%) of 24.
  • Median VISTA score was 50% in epithelioid tumors, compared with 20% in biphasic and 0% in sarcomatoid tumors (p less than 0.001).
  • PD-L1 was found in 115 (38%) of 304 mesotheliomas: sarcomatoid 75% of 24, epithelioid 33% of 240, biphasic 43% of 40.
  • Median PD-L1 score was 20% in sarcomatoid tumors, compared with 0 in biphasic and epithelioid tumors (p less than 0.001).
  • VISTA was expressed in tumor-associated inflammatory cells in 94% of 317 mesotheliomas. PD-L1 was not expressed in these cells in 76% of 303.
  • VISTA and PD-L1 scores in tumor cells showed a weak inverse relationship (r = -0.16; p = 0.004).
  • In multivariate analysis, the score was the percentage of tumor cells staining positive, counted in 10% increments. Each increment for VISTA was associated with better overall survival (HR 0.94, 95% CI 0.91 to 0.98; p = 0.001). Each increment for PD-L1 was associated with worse overall survival (HR 1.1, 95% CI 1.0 to 1.1; p = 0.002). Both results were independent of histology, stage, age and gender.
  • Using a 40% VISTA cutoff, patients with VISTA in more than 40% of tumor cells had 2- and 3-year overall survival of 35.1% and 22.8%. Patients with VISTA in 40% or fewer had 18.7% and 10.0% (univariate HR 0.64; adjusted p = 0.006).
  • The optimal PD-L1 cutoff of 30% gave only marginal evidence of separating patients by survival (adjusted p = 0.078).
• The authors' conclusion: The authors concluded that their data support exploring VISTA as a new immunotherapy target in malignant pleural mesothelioma, especially epithelioid tumors. They also concluded that VISTA expression is an independent prognostic factor for longer survival and PD-L1 for shorter survival.
• Limitations the authors state:
  • Variation within tumors (tumor heterogeneity) is a known confounder for PD-L1 and may also affect VISTA results.
  • Tissue microarrays (small tissue cores) do not allow assessment of the whole tumor.
  • It is unknown how VISTA expression in benign mesothelial cells affects VISTA's usefulness as a treatment target.

Topics

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

Medical terms in this study, explained in our Lexicon: Epithelioid, Pleural Mesothelioma, PD-L1, Immunohistochemistry, Immunotherapy, Biphasic Mesothelioma, Sarcomatoid, Pleura.

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