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Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
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Abstract
Purpose: Programmed death ligand 1 (PD-L1) is expressed in tumor cells and immune cells, and both have been associated with response to anti-PD-1 axis immunotherapy. Here, we examine the expression of PD-L1 to determine which cell type carries the predictive value of the test. Experimental Design: We measured the expression of PD-L1 in multiple immune cells with two platforms and confocal microscopy on three retrospective Yale NSCLC cohorts (425 nonimmunotherapy-treated cases and 62 pembrolizumab/nivolumab/atezolizumab-treated cases). The PD-L1 level was selectively measured in different immune cell subsets using two multiplexed quantitative immunofluorescence panels, including CD56 for natural killer cells, CD68 for macrophages, and CD8 for cytotoxic T cells. Results: PD-L1 was significantly higher in macrophages in both tumor and stromal compartment compared with other immune cells. Elevated PD-L1 in macrophages was correlated with high PD-L1 level in tumor as well as CD8 and CD68 level (P < 0.0001). High PD-L1 expression in macrophages was correlated with better overall survival (OS; P = 0.036 by cell count/P = 0.019 by molecular colocalization), while high PD-L1 expression in tumor cells was not. Conclusions: In nearly 500 non–small cell lung cancer (NSCLC) cases, the predominant immune cell type that expresses PD-L1 is CD68+ macrophages. The level of PD-L1 in macrophages is significantly associated with the level of PD-L1 in tumor cells and infiltration by CD8+ T cells, suggesting a connection between high PD-L1 and “hot” tumors. In anti-PD-1 axis therapy–treated patients, high levels of PD-L1 expression in macrophages are associated with longer OS and may be responsible for the predictive effect of the marker.
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“However, both PDL-1 expression and TMB fail to encapsulate various tumor microenvironmental features influencing ICI responses15–17.”
From Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images (2024) · cites this paper as [17]
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“A previous study by Liu et al. highlighted an example of this complexity, revealing in NSCLC patients treated with ICI that only high PD-L1 expression in macrophages was correlated with better overall survival, while high PD-L1 expression in tumor or stromal cells was not17.”
From Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images (2024) · cites this paper as [17]
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Metadata
- Authors
- Liu, Y., Zugazagoitia, J., Ahmed, F. S., Henick, B. S., Gettinger, S. N., Herbst, R. S., Schalper, K. A., & Rimm, D. L.
- Affiliations
- Yale University (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Rimm, David L.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-02-14
- Volume
- 26
- Issue
- 4
- Pages
- 970-977
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7024671
- OpenAlex
- W2980933209
- Cited by
- 322
- References
- 34
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 65 · 2023: 59 · 2022: 64 · 2021: 50 · 2020: 25
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale SPORE in Lung Cancer (P50-CA196530)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- PD-L1, tumor-associated macrophages, PD-1 pathway blockade, non-small cell lung cancer, pembrolizumab, nivolumab, atezolizumab, predictive biomarkers, CD8+ T cells, tumor immune microenvironment, overall survival
- MeSH terms
- Antineoplastic Agents, Immunological, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Killer Cells, Natural, Lung Neoplasms, Macrophages, Male, Neoplasm Staging, Retrospective Studies, Biomarkers, Tumor, Survival Rate, CD8-Positive T-Lymphocytes, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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