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Cited by 2,324Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy

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Taube, Janis M., Klein, Alison, Brahmer, Julie R., Xu, Haiying, Pan, Xiaoyu, Kim, Jung H., Chen, Lieping, Pardoll, Drew M. +2 more·2014·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-13-3271PMC PMC4185001

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Abstract

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design: Patients (N = 41) with melanoma, non–small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti–PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti–PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade. Clin Cancer Res; 20(19); 5064–74. ©2014 AACR.

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  • The diversity of TME has made it possible to perform immune classification of cancers regarding prognosis, chemotherapy, and immunotherapy response prediction.

    “The diversity of TME has made it possible to perform immune classification of cancers regarding prognosis5, chemotherapy6, and immunotherapy7 response prediction.”

    From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [7]

    The Results report that tumor-cell PD-L1 expression correlated with response to anti-PD-1 therapy, supporting the immunotherapy-response part of the claim. The Discussion calls this finding preliminary and does not establish a general immune classification of cancers for predicting immunotherapy response. The prognosis and chemotherapy portions are attached to other citations, not this source. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • TME makes great contribution to chemotherapy and immunotherapy sensitivity.

    “Given that TME also makes great contribution to chemotherapy and immunotherapy sensitivity7,19,20”

    From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [7]

    The Results report that tumor-cell PD-L1 expression correlated with response to anti-PD-1 therapy, supporting a role for a tumor-microenvironment feature in immunotherapy response. The Discussion also notes improved benefit from certain chemotherapy regimens among HER2-positive breast cancer patients with tumor-infiltrating lymphocytes. These specific associations do not establish the broader claim that the tumor microenvironment makes a major contribution to sensitivity to chemotherapy and immunotherapy generally; several other microenvironmental features did not independently correlate with anti-PD-1 response. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Taube, J. M., Klein, A., Brahmer, J. R., Xu, H., Pan, X., Kim, J. H., Chen, L., Pardoll, D. M., Topalian, S. L., & Anders, R. A.
Affiliations
  • Departments of 1Dermatology,
  • Johns Hopkins University (US)
  • 3Oncology, and
  • Yale University (US)
  • 2Pathology,
Corresponding author
  • Taube, Janis M.
  • Topalian, Suzanne L.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-09-30
Volume
20
Issue
19
Pages
5064-5074
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-13-3271
PMC
PMC4185001
OpenAlex
W2109485845
Cited by
2,324
References
3
Citations by year
2026: 37 · 2025: 95 · 2024: 112 · 2023: 142 · 2022: 169 · 2021: 235 · 2020: 237 · 2019: 206 · 2018: 266 · 2017: 301 · 2016: 281 · 2015: 196 · 2014: 43 · 2013: 2
FWCI
132.21
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Association for Cancer Research
  • Johns Hopkins University
  • Jounce Therapeutics
  • National Cancer Institute (P50CA062924, R01CA142779, P50CA121974)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
PD-1, PD-L1, PD-L2, tumor immune microenvironment, anti-PD-1 therapy, nivolumab, predictive biomarkers, tumor-infiltrating lymphocytes, melanoma, non-small cell lung cancer, renal cell carcinoma, colorectal cancer, castration-resistant prostate cancer, immune cell infiltration, treatment response
MeSH terms
Nivolumab, Antibodies, Monoclonal, Antineoplastic Agents, Biopsy, Humans, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Gene Expression, Lymphocytes, Tumor-Infiltrating, Treatment Outcome, Molecular Targeted Therapy, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein

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