Cited by 323Cancer Immunotherapy and BiomarkersImmune cells in cancerFerroptosis and cancer prognosis

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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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Liu, Yuting, Zugazagoitia, Jon, Ahmed, Fahad Shabbir, Henick, Brian S., Gettinger, Scott N., Herbst, Roy S., Schalper, Kurt A., Rimm, David L.·2020·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-19-1040PMC PMC7024671

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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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Additional file 8 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
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Additional file 5 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
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Additional file 9 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733738
Additional file 2 of Inducing expression of ICOS-L by oncolytic adenovirus to enhance tumor-specific bi-specific antibody efficacy
Saffarzadeh, N., Foord, E., O’Leary, E., Mahmoun, R., Birkballe Hansen, T., Levitsky, V., Poiret, T., & Uhlin, M. (2024) · Figshare · doi:10.6084/m9.figshare.25367510
Additional file 6 of Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion
Wu, X., Cheng, Y.-S. L., Matthen, M., Yoon, A., Schwartz, G. K., Bala, S., Taylor, A. M., & Momen‐Heravi, F. (2021) · Figshare · doi:10.6084/m9.figshare.14052867
Additional file 7 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733732
Additional file 3 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733720
Additional file 2 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733717
Additional file 1 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733714
Additional file 1 of PD-L1 blockade TAM-dependently potentiates mild photothermal therapy against triple-negative breast cancer
Wang, C., Xu, Y.-H., Xu, H.-Z., Li, K., Zhang, Q., Shi, L., Zhao, L., & Chen, X. (2024) · Figshare · doi:10.6084/m9.figshare.26651859
Additional file 1 of An atlas of cell-type-specific interactome networks across 44 human tumor types
Li, Z., Liu, G., Yang, X., Shu, M., Jin, W., Tong, Y., Liu, X., Wang, Y., Yuan, J., & Yang, Y. (2024) · Figshare · doi:10.6084/m9.figshare.25210504
Additional file 6 of ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages
Hua, X., Xu, Q., Wu, R., Sun, W., Gu, Y., Zhu, S., Liu, X., Lv, T., & Song, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26733729

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: Liu, Yuting
Zugazagoitia, Jon
Ahmed, Fahad Shabbir
Henick, Brian S.
Gettinger, Scott N.
Herbst, Roy S.
Schalper, Kurt A.
Rimm, David L.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2020-02-14
Volume: 26
Issue: 4
Pages: 970-977
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-19-1040
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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Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy

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