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J Immunother Cancer. 2018 Oct 1;6(1):99. doi: 10.1186/s40425-018-0404-0.

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.

Author information

1
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.
4
Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
5
Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Division of Dermatology, Department of Medicine, University of Washington Medical Center, Seattle, WA, USA.
7
Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
8
Merck Research Laboratories, Kenilworth, NJ, USA.
9
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jtaube1@jhmi.edu.
11
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jtaube1@jhmi.edu.
12
Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jtaube1@jhmi.edu.
13
The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA. jtaube1@jhmi.edu.

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.

KEYWORDS:

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

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