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Clinical significance of PD-L1 protein expression on tumor-associated macrophages in lung cancer
© Schalper et al. 2015
Published: 4 November 2015
Tumor PD-L1 expression is associated with increased tumor-infiltrating lymphocytes (TILs) in diverse solid tumors, including lung cancer. In addition, PD-L1 upregulation in tumor and/or stromal immune cells has been associated with increased clinical benefit to PD-1/PD-L1 axis blockers. The significance of PD-L1 expression in different immune cell subpopulations at the tumor microenvironment remains poorly understood. Here, we measured PD-L1 protein specifically in tumor-associated macrophages using objective methods and analyzed its clinical significance in human lung cancer.
Using multiplexed quantitative immunofluorescence (QIF) we measured the levels of PD-L1 protein (clone-E1L3N, Cell Signaling technology) in 554 stages I-IV FFPE lung carcinomas represented in two tissue-microarrays, one from Yale University [YTMA79, n=204] and one from Greece [YTMA140, n=350]. PD-L1 was measured using multispectral QIF in CD68-positive cells (macrophages, clone-KP1, DAKO) or in tumor cells (clone-AE1/AE3, DAKO) based on fluorescence co-localization. The levels of CD3 (T cells, clone-E272, Novus), CD8 (cytotoxic T cells, clone-C8/144B, DAKO) and CD20 (B-lymphoctes, clone-L26, DAKO) were also determined in the tumor samples. Associations between the macrophage and tumor PD-L1 levels, clinico-pathological variables and survival were analyzed.
In lung cancer samples, PD-L1 was detected in both macrophages and tumor cells with a predominant membranous staining pattern. Overall, the levels of PD-L1 in the CD68+ population were lower than in tumor cells in both cohorts (834 ± 314 AU vs 1113 ± 427 AU, in the Yale cohort, P < 0.001; and 895 ± 451 AU vs 1069 ± 542 AU in the Greek set, P < 0.001). In both collections, the macrophage and tumor PD-L1 signal showed a positive non-linear association (Linear regression coefficient [R2]=0.311 in the Yale cohort and R2=0.43 in the Greek collection). Using the median score as cutpoint, elevated macrophage PD-L1 content was significantly associated with high CD8+ and CD20+ cells in both cohorts. In addition, increased macrophage PD-L1 signal was marginally associated with longer overall survival in the Yale set (HR=0.676 [CI:0.450-1.081], P=0.05), but not in the Greek group (HR=0.790 [CI:0.560-1.109], P=0.17).
PD-L1 is expressed in tumor-associated macrophages of human lung carcinomas. The macrophage PD-L1 signal is lower than in tumor epithelial cells and they show a positive association. Elevated macrophage PD-L1 is prominently associated with increased cytotoxic T lymphocytes and B cell infiltrates in lung tumors, but has limited prognostic value. Further studies will be required to evaluate the possible predictive role of PD-L1 expression in macrophages and other immune cell types.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.