Expression and clinical significance of VISTA and PD-L1 in adrenocortical carcinoma

in Endocrine-Related Cancer
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  • 1 Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
  • | 2 Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
  • | 3 Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
  • | 4 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
  • | 5 Department of Endocrinology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Graduate School of Peking Union Medical College, Nanjing, China

Correspondence should be addressed to P Li or Y Bi: li78321@yeah.net or biyan@nju.edu.cn

*(Z Zhang and M Li contributed equally to this work)

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Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and challenging management. The present study aimed to investigate the expression of programmed death ligand-1 (PD-L1) and V-domain Ig-containing suppressor of T cell activation (VISTA) in ACC and their associations with clinicopathological features and survival outcomes. Immunohistochemistry was performed on formalin-fixed paraffin-embedded specimens from 54 ACC patients. Chi-square/Fisher’s exact tests or independent samples t/Mann–Whitney U tests were performed to assess correlations between immunoscores and clinicopathological parameters. The Kaplan–Meier method and Cox regression were conducted for survival analysis and to identify independent predictors of overall (OS) and disease-free (DFS) survival. Results showed that VISTA was expressed in tumor cells (TCs) and tumor-infiltrating immune cells (TICs) in 81.5% (44/54) and 40.7% (22/54) of the patients, respectively. PD-L1 positivity was found in either TCs or TICs in 11.1% (6/54) of the patients. Patients with positive VISTA expression in TCs had a higher tumor stage (56.9% vs 20%, P  = 0.036) and Ki-67 index (30.50 ± 23.51% vs 14.76 ± 11.75%, P  = 0.006). However, PD-L1 positivity in either TCs or TICs had no association with patient clinicopathological features. A higher VISTA expression intensity, a larger area and a higher immunoscore were associated with increased risks of disease progression and overall mortality, but PD-L1 expression in TCs or TICs was not associated with OS or DFS. In conclusion, positive TC VISTA expression was correlated with pathological parameters related to malignancy in ACC patients. This finding provides novel evidence of the value of VISTA, in addition to PD-L1, as an immunotherapeutic target in ACC.

 

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  • Altieri B, Ronchi CL, Kroiss M & Fassnacht M 2020 Next-generation therapies for adrenocortical carcinoma. Best Practice and Research: Clinical Endocrinology and Metabolism 34 101434. (https://doi.org/10.1016/j.beem.2020.101434)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Berruti A, Tiberio GAM & Sigala S 2021 Adrenocortical carcinoma. Cancers 13 1077. (https://doi.org/10.3390/cancers13051077)

  • Billon E, Finetti P, Bertucci A, Niccoli P, Birnbaum D, Mamessier E & Bertucci F 2019 PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma. Oncoimmunology 8 e1655362. (https://doi.org/10.1080/2162402X.2019.1655362)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bisceglia M, Ludovico O, Di Mattia A, Ben-Dor D, Sandbank J, Pasquinelli G, Lau SK & Weiss LM 2004 Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. International Journal of Surgical Pathology 12 231243. (https://doi.org/10.1177/106689690401200304)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Böger C, Behrens HM, Krüger S & Röcken C 2017 The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: a future perspective for a combined gastric cancer therapy? Oncoimmunology 6 e1293215. (https://doi.org/10.1080/2162402X.2017.1293215)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao X, Ren X, Zhou Y, Mao F, Lin Y, Wu H & Sun Q 2020 VISTA expression on immune cells correlates with favorable prognosis in patients with triple-negative breast cancer. Frontiers in Oncology 10 583966. (https://doi.org/10.3389/fonc.2020.583966)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, Kirschner LS, Chae YK, Abdulkadir SA & Rademaker A et al.2019 Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. Journal of Clinical Endocrinology and Metabolism 104 61936200. (https://doi.org/10.1210/jc.2019-00600)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choi JW, Kim YJ, Yun KA, Won CH, Lee MW, Choi JH, Chang SE & Lee WJ 2020 The prognostic significance of VISTA and CD33-positive myeloid cells in cutaneous melanoma and their relationship with PD-1 expression. Scientific Reports 10 14372. (https://doi.org/10.1038/s41598-020-71216-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crona J & Beuschlein F 2019 Adrenocortical carcinoma – towards genomics guided clinical care. Nature Reviews: Endocrinology 15 548560. (https://doi.org/10.1038/s41574-019-0221-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • ElTanbouly MA, Zhao Y, Schaafsma E, Burns CM, Mabaera R, Cheng C & Noelle RJ 2020 VISTA: a target to manage the innate cytokine storm. Frontiers in Immunology 11 595950. (https://doi.org/10.3389/fimmu.2020.595950)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, Haak HR, Mihai R, Assie G & Terzolo M 2018 European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. European Journal of Endocrinology 179 G1G46. (https://doi.org/10.1530/EJE-18-0608)

    • Search Google Scholar
    • Export Citation
  • Fay AP, Signoretti S, Callea M, Telό GH, McKay RR, Song J, Carvo I, Lampron ME, Kaymakcalan MD & Poli-de-Figueiredo CE et al.2015 Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. Journal for ImmunoTherapy of Cancer 3 3. (https://doi.org/10.1186/s40425-015-0047-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M & Young WF 2016 The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 101 18891916. (https://doi.org/10.1210/jc.2015-4061)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H & Efstathiou E et al.2017 VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nature Medicine 23 551555. (https://doi.org/10.1038/nm.4308)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, Rodon Ahnert J, Jimenez C, Lee JE & Perrier ND et al.2019 Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. Journal for ImmunoTherapy of Cancer 7 253. (https://doi.org/10.1186/s40425-019-0722-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • He HX, Gao Y, Fu JC, Zhou QH, Wang XX, Bai B, Li PF, Huang C, Rong QX & Ping LQ et al.2021 VISTA and PD-L1 synergistically predict poor prognosis in patients with extranodal natural killer/T-cell lymphoma. Oncoimmunology 10 1907059. (https://doi.org/10.1080/2162402X.2021.1907059)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hong S, Yuan Q, Xia H, Zhu G, Feng Y, Wang Q, Zhang Z, He W, Lu J & Dong C et al.2019 Analysis of VISTA expression and function in renal cell carcinoma highlights VISTA as a potential target for immunotherapy. Protein and Cell 10 840845. (https://doi.org/10.1007/s13238-019-0642-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hosseinkhani N, Derakhshani A, Shadbad MA, Argentiero A, Racanelli V, Kazemi T, Mokhtarzadeh A, Brunetti O, Silvestris N & Baradaran B 2021 The role of V-domain Ig suppressor of T cell activation (VISTA) in cancer therapy: lessons learned and the road ahead. Frontiers in Immunology 12 676181. (https://doi.org/10.3389/fimmu.2021.676181)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang X, Zhang X, Li E, Zhang G, Wang X, Tang T, Bai X & Liang T 2020 VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. Journal of Hematology and Oncology 13 83. (https://doi.org/10.1186/s13045-020-00917-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, Thompson JF, Wilmott JS, Long GV & Scolyer RA 2017 Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Modern Pathology 30 16661676. (https://doi.org/10.1038/modpathol.2017.89)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karwacka I, Obołończyk Ł, Kaniuka-Jakubowska S & Sworczak K 2021 The role of immunotherapy in the treatment of adrenocortical carcinoma. Biomedicines 9 98. (https://doi.org/10.3390/biomedicines9020098)

    • Search Google Scholar
    • Export Citation
  • Klein O, Senko C, Carlino MS, Markman B, Jackett L, Gao B, Lum C, Kee D, Behren A & Palmer J et al.2021 Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. Oncoimmunology 10 1908771. (https://doi.org/10.1080/2162402X.2021.1908771)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, Wermke M, Hariharan S, von Heydebreck A & Kasturi V et al.2018 Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. Journal for ImmunoTherapy of Cancer 6 111. (https://doi.org/10.1186/s40425-018-0424-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu S, Ding G, Zhou Z & Feng C 2018 β-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion. OncoTargets and Therapy 11 20292036. (https://doi.org/10.2147/OTT.S159979)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Loeser H, Kraemer M, Gebauer F, Bruns C, Schröder W, Zander T, Persa OD, Alakus H, Hoelscher A & Buettner R et al.2019 The expression of the immune checkpoint regulator VISTA correlates with improved overall survival in pT1/2 tumor stages in esophageal adenocarcinoma. Oncoimmunology 8 e1581546. (https://doi.org/10.1080/2162402X.2019.1581546)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mulati K, Hamanishi J, Matsumura N, Chamoto K, Mise N, Abiko K, Baba T, Yamaguchi K, Horikawa N & Murakami R et al.2019 VISTA expressed in tumour cells regulates T cell function. British Journal of Cancer 120 115127. (https://doi.org/10.1038/s41416-018-0313-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mutsaers P, Balcioglu HE, Kuiper R, Hammerl D, Wijers R, Van Duin M, Van Der Holt B, Broijl A, Gregory W & Zweegman S et al.2021 V-domain Ig suppressor of T cell activation (VISTA) expression is an independent prognostic factor in multiple myeloma. Cancers 13 2219. (https://doi.org/10.3390/cancers13092219)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A & Endocrine Society 2015 Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 100 28072831. (https://doi.org/10.1210/jc.2015-1818)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Parise IZS, Parise GA, Noronha L, Surakhy M, Woiski TD, Silva DB, Costa TEB, Del-Valle MHCP, Komechen H & Rosati R et al.2019 The prognostic role of CD8+ T lymphocytes in childhood adrenocortical carcinomas compared to Ki-67, PD-1, PD-L1, and the Weiss score. Cancers 11 1730. (https://doi.org/10.3390/cancers11111730)

    • Search Google Scholar
    • Export Citation
  • Pęksa R, Kunc M, Popęda M, Piątek M, Bieńkowski M, Żok J, Starzyńska A, Perdyan A, Sowa M & Duchnowska R et al.2021 Combined assessment of immune checkpoint regulator VISTA on tumor-associated immune cells and platelet-to-lymphocyte ratio identifies advanced germ cell tumors with higher risk of unfavorable outcomes. Cancers 13 1750. (https://doi.org/10.3390/cancers13081750)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, Capanu M, Zamarin D, Saltz LB & Ariyan CE et al.2020 PD-1 blockade in advanced adrenocortical carcinoma. Journal of Clinical Oncology 38 7180. (https://doi.org/10.1200/JCO.19.01586)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shimada H, Yamazaki Y, Sugawara A, Sasano H & Nakamura Y 2021 Molecular mechanisms of functional adrenocortical adenoma and carcinoma: genetic characterization and intracellular signaling pathway. Biomedicines 9 892. (https://doi.org/10.3390/biomedicines9080892)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tagliamento M, Bironzo P & Novello S 2020 New emerging targets in cancer immunotherapy: the role of VISTA. ESMO Open 4 e000683. (https://doi.org/10.1136/esmoopen-2020-000683)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, Syrigos K, Toki M, Zhao H & Chen L et al.2018 Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clinical Cancer Research 24 15621573. (https://doi.org/10.1158/1078-0432.CCR-17-2542)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang L, Jia B, Claxton DF, Ehmann WC, Rybka WB, Mineishi S, Naik S, Khawaja MR, Sivik J & Han J et al.2018 VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML. Oncoimmunology 7 e1469594. (https://doi.org/10.1080/2162402X.2018.1469594)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Weiss LM 1984 Comparative histologic study of 43 metastasizing and nonetastasizing adrenocortical tumors. American Journal of Surgical Pathology 8 163169. (https://doi.org/10.1097/00000478-198403000-00001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yuan L, Tatineni J, Mahoney KM & Freeman GJ 2021 VISTA: a mediator of quiescence and a promising target in cancer immunotherapy. Trends in Immunology 42 209227. (https://doi.org/10.1016/j.it.2020.12.008)

    • Search Google Scholar
    • Export Citation
  • Zhang M, Pang HJ, Zhao W, Li YF, Yan LX, Dong ZY & He XF 2018 VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer 18 511. (https://doi.org/10.1186/s12885-018-4435-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zong L, Zhou Y, Zhang M, Chen J & Xiang Y 2020 VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer. Cancer Immunology, Immunotherapy 69 3342. (https://doi.org/10.1007/s00262-019-02434-5)

    • PubMed
    • Search Google Scholar
    • Export Citation