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VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

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Abstract

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson’s correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

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Abbreviations

AJCC:

American Joint Committee on Cancer

CI:

Confidence interval

HR:

Hazard ratio

TCGA:

The cancer genome atlas

TIIC:

Tumor-infiltrating inflammatory cells

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Funding

This work was supported by National Cancer Institute Grant NCI P30CA023108, Dartmouth Hitchcock Melanoma Funds, and funding provided by Immunext. In addition, Dr. Randolph Noelle has support from NCI RO1 AI098007 and NCI RO1 CA214062, Dr. Mary Jo Turk from NCI RO1 CA214062, and Dr. Marc Ernstoff from NCI PO1 CA206980 and NCI P30 CA016056.

Author information

Author notes

  1. Lawrence F. Kuklinski and Shaofeng Yan equally contributing first authors.

Authors and Affiliations

  1. Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Lawrence F. Kuklinski

  2. Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA

    Lawrence F. Kuklinski

  3. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Shaofeng Yan

  4. Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, USA

    Zhongze Li

  5. Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Jan L. Fisher

  6. Departments of Biomedical Data Sciences, Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, USA

    Chao Cheng

  7. Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Randolph J. Noelle & Mary Jo Turk

  8. Department of Surgery, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Christina V. Angeles

  9. Roswell Park Cancer Institute, University of Buffalo, The State University of New York, Elm and Carlton, Buffalo, NY, 14263, USA

    Marc S. Ernstoff

Authors
  1. Lawrence F. Kuklinski
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  2. Shaofeng Yan
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  3. Zhongze Li
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  4. Jan L. Fisher
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  5. Chao Cheng
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  6. Randolph J. Noelle
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  8. Mary Jo Turk
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  9. Marc S. Ernstoff
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Contributions

LFK: interpreted data and wrote the manuscript. SY: conceived the study, interpreted data, and wrote the manuscript. ZL: analyzed data. JLF: interpreted data and wrote the manuscript. CC: analyzed data. RJN: edited the manuscript. CVA: edited the manuscript. MJT: edited the manuscript. MSE: conceived and supervised the study, interpreted data, and wrote the manuscript.

Corresponding author

Correspondence to Marc S. Ernstoff.

Ethics declarations

Conflict of interest

Randolph J. Noelle is the co-founder of ImmuNext. All other authors declare no conflicts of interest.

Ethical approval

This study was approved by the Dartmouth College Committee for the Protection of Human Subjects/Institutional Review Board, approval number 23388, and was in compliance with ethical guidelines according to the Declaration of Helsinki.

Informed consent

Informed consent was waived by the Institutional Review Board on the grounds of being a retrospective study using tumor tissue already archived by the Dartmouth-Hitchcock Medical Center Department of Pathology tumor bank. Many patients were deceased. All data was abstracted from the medical record and had previously been obtained for the purposes of medical care.

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Kuklinski, L.F., Yan, S., Li, Z. et al. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother 67, 1113–1121 (2018). https://doi.org/10.1007/s00262-018-2169-1

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  • DOI: https://doi.org/10.1007/s00262-018-2169-1

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