Abstract
BackgroundWe 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.MethodsPretreatment 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.ResultsTumors 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.ConclusionsWhile 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.
Highlights
We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab
CD8+ tumor-infiltrating lymphocytes (TIL) [4, 6] and tumor cell progressive disease (PD)-L1 expression [7] have been associated with improved patient survival, indicating that the immune system is able to exert some control over this aggressive neoplasm
We found that the simple presence or absence of tumor cell PD-L1 expression in MCC did not correlate with anti-PD-1 response [11]
Summary
We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. The interaction between PD-1 and its ligands downregulates immune cell activation, proliferation, survival and cytokine production [8, 9]. For this reason, therapeutic blockade of the PD-1/PD-L1 checkpoint has been embraced as a strategy to enhance antitumor immunity, with durable efficacy in some patients with multiple tumor types [10]. We recently reported that patients with advanced MCC receiving first-line treatment with pembrolizumab (anti-PD-1) experienced an objective response rate of 56% [11]. While it is assumed that PD-1 is mostly involved in regulation of CD8+ T-cell activity in the TME, we discerned multiple immune cell subsets which may contribute to PD-1 biomarker relevance
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