The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
Open accessPublished version of a preprint
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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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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PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Herbst, R. S., Soria, J.-C., Kowanetz, M., Fine, G. D., Hamid, O., Gordon, M. S., Sosman, J. A., McDermott, D. F., Powderly, J. D., Gettinger, S. N., et al. (2014) · Nature · doi:10.1038/nature14011 · Cited by 5,231
Self-citationTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025
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The PD‐1 pathway in tolerance and autoimmunity
Francisco, L. M., Sage, P. T., & Sharpe, A. H. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00923.x · Cited by 2,300
The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection
Sharpe, A. H., Wherry, E. J., Ahmed, R., & Freeman, G. J. (2007) · Nature Immunology · doi:10.1038/ni1443 · Cited by 1,559
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity
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Self-citationThe Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker
Jardim, D. L., Goodman, A., de Melo Gagliato, D., & Kurzrock, R. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.10.001 · Cited by 1,192
Regulatory mechanisms of PD-1/PD-L1 in cancers
Lin, X., Kang, K., Chen, P., Zeng, Z., Li, G., Xiong, W., Yi, M., & Xiang, B. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02023-w · Cited by 909
The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies
Petitprez, F., Meylan, M., de Reyniès, A., Sautès‐Fridman, C., & Fridman, W. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00784 · Cited by 621
Li, F., Li, C., Cai, X., Xie, Z., Zhou, L., Cheng, B., Zhong, R., Xiong, S., Li, J., Chen, Z., et al. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.101134 · Cited by 376
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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