Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab 11 Medical and Health Sciences 1107 Immunology

Nicolas A. Giraldo, Peter Nguyen, Elizabeth L. Engle, Genevieve J. Kaunitz, Tricia R. Cottrell, Sneha Berry, Benjamin Green, Abha Soni, Jonathan D. Cuda, Julie E. Stein, Joel C. Sunshine, Farah Succaria, Haiying Xu, Aleksandra Ogurtsova, Liudmila V Danilova, Candice D. Church, Natalie J. Miller, Steve Fling, Lisa Lundgren, Nirasha RamchurrenJennifer H. Yearley, Evan Lipson, Mac Cheever, Robert A Anders, Paul T. Nghiem, Suzanne Topalian, Janis M Taube

Research output: Contribution to journalArticle

Abstract

Background: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. Methods: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. Results: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. Conclusions: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

Original languageEnglish (US)
Article number99
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - Oct 1 2018

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Merkel Cell Carcinoma
Allergy and Immunology
Health
Cell Count
pembrolizumab
T-Lymphocytes
Neoplasms
Fluorescent Antibody Technique
B-Lymphocytes
Biomarkers
Immunohistochemistry

Keywords

  • Merkel cell
  • Multispectral immunofluorescence
  • PD-1
  • PD-L1
  • Pembrolizumab

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab 11 Medical and Health Sciences 1107 Immunology. / Giraldo, Nicolas A.; Nguyen, Peter; Engle, Elizabeth L.; Kaunitz, Genevieve J.; Cottrell, Tricia R.; Berry, Sneha; Green, Benjamin; Soni, Abha; Cuda, Jonathan D.; Stein, Julie E.; Sunshine, Joel C.; Succaria, Farah; Xu, Haiying; Ogurtsova, Aleksandra; Danilova, Liudmila V; Church, Candice D.; Miller, Natalie J.; Fling, Steve; Lundgren, Lisa; Ramchurren, Nirasha; Yearley, Jennifer H.; Lipson, Evan; Cheever, Mac; Anders, Robert A; Nghiem, Paul T.; Topalian, Suzanne; Taube, Janis M.

In: Journal for ImmunoTherapy of Cancer, Vol. 6, No. 1, 99, 01.10.2018.

Research output: Contribution to journalArticle

Giraldo, NA, Nguyen, P, Engle, EL, Kaunitz, GJ, Cottrell, TR, Berry, S, Green, B, Soni, A, Cuda, JD, Stein, JE, Sunshine, JC, Succaria, F, Xu, H, Ogurtsova, A, Danilova, LV, Church, CD, Miller, NJ, Fling, S, Lundgren, L, Ramchurren, N, Yearley, JH, Lipson, E, Cheever, M, Anders, RA, Nghiem, PT, Topalian, S & Taube, JM 2018, 'Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab 11 Medical and Health Sciences 1107 Immunology', Journal for ImmunoTherapy of Cancer, vol. 6, no. 1, 99. https://doi.org/10.1186/s40425-018-0404-0
Giraldo, Nicolas A. ; Nguyen, Peter ; Engle, Elizabeth L. ; Kaunitz, Genevieve J. ; Cottrell, Tricia R. ; Berry, Sneha ; Green, Benjamin ; Soni, Abha ; Cuda, Jonathan D. ; Stein, Julie E. ; Sunshine, Joel C. ; Succaria, Farah ; Xu, Haiying ; Ogurtsova, Aleksandra ; Danilova, Liudmila V ; Church, Candice D. ; Miller, Natalie J. ; Fling, Steve ; Lundgren, Lisa ; Ramchurren, Nirasha ; Yearley, Jennifer H. ; Lipson, Evan ; Cheever, Mac ; Anders, Robert A ; Nghiem, Paul T. ; Topalian, Suzanne ; Taube, Janis M. / Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab 11 Medical and Health Sciences 1107 Immunology. In: Journal for ImmunoTherapy of Cancer. 2018 ; Vol. 6, No. 1.
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abstract = "Background: We recently reported a 56{\%} objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. Methods: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. Results: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. Conclusions: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.",
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T1 - Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab 11 Medical and Health Sciences 1107 Immunology

AU - Giraldo, Nicolas A.

AU - Nguyen, Peter

AU - Engle, Elizabeth L.

AU - Kaunitz, Genevieve J.

AU - Cottrell, Tricia R.

AU - Berry, Sneha

AU - Green, Benjamin

AU - Soni, Abha

AU - Cuda, Jonathan D.

AU - Stein, Julie E.

AU - Sunshine, Joel C.

AU - Succaria, Farah

AU - Xu, Haiying

AU - Ogurtsova, Aleksandra

AU - Danilova, Liudmila V

AU - Church, Candice D.

AU - Miller, Natalie J.

AU - Fling, Steve

AU - Lundgren, Lisa

AU - Ramchurren, Nirasha

AU - Yearley, Jennifer H.

AU - Lipson, Evan

AU - Cheever, Mac

AU - Anders, Robert A

AU - Nghiem, Paul T.

AU - Topalian, Suzanne

AU - Taube, Janis M

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. Methods: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. Results: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. Conclusions: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

AB - Background: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. Methods: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. Results: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. Conclusions: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

KW - Merkel cell

KW - Multispectral immunofluorescence

KW - PD-1

KW - PD-L1

KW - Pembrolizumab

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