Abstract
Simple SummaryMost patients with advanced non-small cell lung cancer (NSCLC) do not respond to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis blockade, highlighting the need for the identification of new targets for immune checkpoint inhibition. In this study, we used quantitative immunofluorescence to characterize the CD200/CD200R immune checkpoint in lung cancer. We described a careful validation of antibody probes for this pair and found CD200 and CD200R to be overexpressed in 29.7% and 25% of NSCLC patients, respectively; stromal expression of CD200R was significantly increased in patients with squamous histology. Additionally, we showed that PD-L1 was moderately correlated with CD200 but only weakly correlated with CD200R. As new drugs targeting the CD200/CD200R interaction enter into clinical trials in humans, this work identifies this immune checkpoint as a potential target for patients with NSCLC and lays the groundwork for the development of a clinical companion diagnostic test.CD200/CD200R is an immune checkpoint with broad expression patterns and a potential target for immune therapy. In this study, we assess both CD200 and CD200R expression in solid tumors, with a focus on lung cancer, and evaluate their association with clinicopathologic characteristics, mutation status, outcome, and programmed death-ligand 1 (PD-L1) expression. We used multiplexed quantitative immunofluorescence (QIF) to measure the expression of CD200 and CD200R in a total of 455 patients from three lung cancer cohorts. Using carefully validated antibodies, we performed target measurement with tyramide-based QIF panels and analyzed the data using the PM2000 microscope and AQUA software. CD200 tumor positivity was found in 29.7% of non-small cell lung cancer (NSCLC) patients and 33.3% of lung large cell neuroendocrine carcinoma (LCNEC) patients. CD200 demonstrated notable intratumoral heterogeneity. CD200R was expressed in immune cells in 25% of NSCLC and 41.3% of LCNEC patients. While CD200R is predominantly expressed in immune cells, rare tumor cell staining was seen in a highly heterogeneous pattern. CD200R expression in the stromal compartment was significantly higher in patients with squamous differentiation (p < 0.0001). Neither CD200 nor CD200R were associated with other clinicopathologic characteristics or mutation status. Both biomarkers were not prognostic for disease-free or overall survival in NSCLC. CD200 showed moderate correlation with PD-L1. CD200/CD200R pathway is frequently expressed in lung cancer patients. Differential expression patterns of CD200 and CD200R with PD-L1 suggest a potential role for targeting this pathway alone in patients with NSCLC.
Highlights
Immune checkpoint blockade has become the new standard in the treatment of advanced-stage non-small cell lung cancer (NSCLC)
For the anti-CD200 receptor (CD200R) antibody validation process, we used two different antibodies targeting non-overlapping epitopes of the extracellular domain of human CD200R, Lilly antibody 1 and Lilly antibody 2 (Eli Lilly and Company) (Table S6). We titrated these antibodies in a NSCLC array (YTMA295) containing 35 tumor cores with presumed variable CD200R expression (Figure S1A,B)
We observed CD200R staining within the stromal compartment, with membranous localization of signal (Figure S1C–E)
Summary
Immune checkpoint blockade has become the new standard in the treatment of advanced-stage non-small cell lung cancer (NSCLC). Even when combined with standard platinum-based chemotherapy, only 47.6% of NSCLC patients respond to PD-1/PD-L1 axis inhibitors [2] These profound and durable responses, yet limited to a restricted number of patients, have underlined the need of identifying new potential targets for immune checkpoint inhibition, which could potentially be targeted either alone or in combination with the PD-1/PD-L1 pathway, expanding patient populations that can benefit from immunotherapy. While PD-1/PD-L1 pathway is mostly dependent on modulating T cell activity directly and inducing IFNγ, CD200/CD200R pathway modulates immune activity largely via myeloid suppressive mechanisms and is not dependent solely on IFNγ activity [10,11,12] Both CD200 and CD200R have been thoroughly studied in hematologic malignancies; CD200 is an independent negative prognostic factor for patients with chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), multiple myeloma (MM) and myelodysplastic syndromes (MDS) [13,14,15,16]. We used multiplexed quantitative immunofluorescence (QIF) to assess the distribution and patterns of expression of both CD200 and CD200R in three independent lung cancer cohorts and evaluate their association with clinicopathologic characteristics, mutation status, outcome, and PD-L1 expression
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