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Cancer Immunology Research
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Research Articles

Quantitative Analysis of Immune Infiltrates in Primary Melanoma

Robyn D. Gartrell, Douglas K. Marks, Thomas D. Hart, Gen Li, Danielle R. Davari, Alan Wu, Zoë Blake, Yan Lu, Kayleigh N. Askin, Anthea Monod, Camden L. Esancy, Edward C. Stack, Dan Tong Jia, Paul M. Armenta, Yichun Fu, Daisuke Izaki, Bret Taback, Raul Rabadan, Howard L. Kaufman, Charles G. Drake, Basil A. Horst and Yvonne M. Saenger
Robyn D. Gartrell
1Departments of Pediatrics, Pediatric Hematology/Oncology and Medicine, Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Douglas K. Marks
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Thomas D. Hart
3Columbia University, Columbia College, New York, New York.
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Gen Li
4Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
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Danielle R. Davari
3Columbia University, Columbia College, New York, New York.
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Alan Wu
5Mailman School of Public Health, Columbia University, New York, New York.
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Zoë Blake
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Yan Lu
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Kayleigh N. Askin
3Columbia University, Columbia College, New York, New York.
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Anthea Monod
6Department of Systems Biology, Columbia University, New York, New York.
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Camden L. Esancy
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Edward C. Stack
7PerkinElmer, Hopkinton, Massachusetts.
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Dan Tong Jia
8Columbia University, College of Physician and Surgeons, New York, New York.
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Paul M. Armenta
8Columbia University, College of Physician and Surgeons, New York, New York.
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Yichun Fu
8Columbia University, College of Physician and Surgeons, New York, New York.
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Daisuke Izaki
3Columbia University, Columbia College, New York, New York.
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Bret Taback
9Department of Surgery, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Raul Rabadan
6Department of Systems Biology, Columbia University, New York, New York.
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Howard L. Kaufman
10Department of Surgery, Rutgers Cancer Institute, New York, New York.
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Charles G. Drake
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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Basil A. Horst
11Department of Dermatopathology, Columbia University Medical Center, New York, New York.
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Yvonne M. Saenger
2Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center/New York Presbyterian, New York, New York.
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  • For correspondence: yms4@cumc.columbia.edu
DOI: 10.1158/2326-6066.CIR-17-0360 Published April 2018
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Abstract

Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR−) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR− macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67− tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481–93. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received July 13, 2017.
  • Revision received November 6, 2017.
  • Accepted February 15, 2018.
  • Published first February 21, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Immunology Research: 6 (4)
April 2018
Volume 6, Issue 4
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Quantitative Analysis of Immune Infiltrates in Primary Melanoma
Robyn D. Gartrell, Douglas K. Marks, Thomas D. Hart, Gen Li, Danielle R. Davari, Alan Wu, Zoë Blake, Yan Lu, Kayleigh N. Askin, Anthea Monod, Camden L. Esancy, Edward C. Stack, Dan Tong Jia, Paul M. Armenta, Yichun Fu, Daisuke Izaki, Bret Taback, Raul Rabadan, Howard L. Kaufman, Charles G. Drake, Basil A. Horst and Yvonne M. Saenger
Cancer Immunol Res April 1 2018 (6) (4) 481-493; DOI: 10.1158/2326-6066.CIR-17-0360

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Quantitative Analysis of Immune Infiltrates in Primary Melanoma
Robyn D. Gartrell, Douglas K. Marks, Thomas D. Hart, Gen Li, Danielle R. Davari, Alan Wu, Zoë Blake, Yan Lu, Kayleigh N. Askin, Anthea Monod, Camden L. Esancy, Edward C. Stack, Dan Tong Jia, Paul M. Armenta, Yichun Fu, Daisuke Izaki, Bret Taback, Raul Rabadan, Howard L. Kaufman, Charles G. Drake, Basil A. Horst and Yvonne M. Saenger
Cancer Immunol Res April 1 2018 (6) (4) 481-493; DOI: 10.1158/2326-6066.CIR-17-0360
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