Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 6, Issue -, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1186/s40425-018-0404-0
Keywords
PD-1; PD-L1; Merkel cell; Multispectral immunofluorescence; Pembrolizumab
Categories
Funding
- Melanoma Research Alliance
- Bristol-Myers Squibb
- Sidney Kimmel Cancer Center Core Grant [P30 CA006973]
- National Cancer Institute [R01 CA142779]
- NIH [T32 CA193145, UM1 CA154967]
- NCI [K24 CA139052]
- NIH/NCI Cancer Center Support Grant [P30 CA015704]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Cancer Immunotherapy Trials Network
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant [SU2C-AACR-DT1012]
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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/mm(2), 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 mu m 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, T-regs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.
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