ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- PDCD1 gene polymorphisms linked with altered risk of female-specific hormone-dependent cancers: a systematic review and meta-analysis.BMC cancer · 2026Pooled it
- Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear-Cell Renal Cell Carcinoma: Analyses of the HCRN GU16-260 Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Long-term follow-up from the OMNIVORE trial: response-adaptive nivolumab and ipilimumab in advanced renal cell carcinoma.Journal for immunotherapy of cancer · 2026Trial
- Development of a Classifier for Metabolic Subtypes of Nasopharyngeal Carcinoma to Guide Personalized Immunotherapy Strategies: Biomarker Analysis of the Phase III CONTINUUM and DIPPER Trials.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2026Trial
- The seventh kidney cancer research summit: progress in accelerating cures.The oncologist · 2026Article
- Natural Products in Clear Cell Renal Cell Carcinoma: Rewiring the VHL-HIF Axis, Metabolic Plasticity, and Tumor-Immune Interactions.International journal of molecular sciences · 2026Review
- Selective Nanobody-Derived Minibodies Targeting Galectin-1 and -7 Reveal Non-Redundant Glyco-Immune Functions and Therapeutic Potential in Triple-Negative Breast Cancer.Journal of medicinal chemistry · 2026Article
- Article
- <p>Tumor microenvironment in bone sarcomas: Implications for immunotherapy and emerging therapeutic vulnerabilities (Review)</p>.Oncology reports · 2026Review
- Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression.Molecular cancer · 2026Review
- PD-1, BTLA and TIGIT as therapeutic targets for rheumatic disease.Nature reviews. Rheumatology · 2026Review
- Review
- A bibliometric analysis of resistance to PD-1/PD-L1 inhibitors.Frontiers in immunology · 2026Article
- Immunosuppressive cell populations as potential drivers of extrinsic immune checkpoint inhibition resistance in clear cell renal cell carcinoma.Oncology reviews · 2026Review
- Deciphering the mechanistic landscape of immune checkpoint blockade in ccRCC: from molecular drivers to therapeutic responses.Frontiers in immunology · 2026Review
- The efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes.JHEP reports : innovation in hepatology · 2025Article
- Quantitative analysis of lymphocyte exhaustion markers in patients with localized clear cell renal cell carcinoma.Oncology letters · 2025Article
- Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors.Nature reviews. Nephrology · 2025Review
- Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer.Cancers · 2025Review
- Immuno-Oncology at the Crossroads: Confronting Challenges in the Quest for Effective Cancer Therapies.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
21 authors at 9 institutions in 1 country.
Funding
Abstract
purposeProgrammed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors. EXPERIMENTAL
designPD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).
resultsIn the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus.
conclusionsPD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.