TY - JOUR T1 - Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-018-0404-0 VL - 6 IS - 1 SP - 99 AU - Nicolas A. Giraldo AU - Peter Nguyen AU - Elizabeth L. Engle AU - Genevieve J. Kaunitz AU - Tricia R. Cottrell AU - Sneha Berry AU - Benjamin Green AU - Abha Soni AU - Jonathan D. Cuda AU - Julie E. Stein AU - Joel C. Sunshine AU - Farah Succaria AU - Haiying Xu AU - Aleksandra Ogurtsova AU - Ludmila Danilova AU - Candice D. Church AU - Natalie J. Miller AU - Steve Fling AU - Lisa Lundgren AU - Nirasha Ramchurren AU - Jennifer H. Yearley AU - Evan J. Lipson AU - Mac Cheever AU - Robert A. Anders AU - Paul T. Nghiem AU - Suzanne L. Topalian AU - Janis M. Taube Y1 - 2018/12/01 UR - http://jitc.bmj.com/content/6/1/99.abstract 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. ER -