PD-1 blockade induces responses by inhibiting adaptive immune resistance
Open accessAbstract
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance). Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
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Both PD-L1 expression and TMB fail to encapsulate various tumor microenvironmental features influencing ICI responses.
“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 [15]
The paper’s Abstract and Extended Data Figures 4–5 link pembrolizumab response to CD8-cell location, PD-1/PD-L1 expression and T-cell repertoire features, supporting the point that PD-L1 expression alone does not capture every relevant microenvironmental feature. Our copy does not assess tumor mutational burden (TMB) or whether it fails to capture those features. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPre-treatment CD8+ T cell presence is linked to responses to ICB and anti-PD-1 plus lenvatinib in HCC patients.
“Pre-treatment CD8+ T cell presence is linked to responses to ICB and anti-PD-1 plus lenvatinib in HCC patients.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [4]
The Abstract reports that higher pre-treatment CD8+ T-cell numbers were associated with response to PD-1 blockade. However, the patients had metastatic melanoma and received pembrolizumab; the paper does not establish this association for anti-PD-1 plus lenvatinib in HCC patients. (LLM, conf=0.91)
Experimental — accuracy not yet measuredHigher density of CD8+ T cells was observed in baseline tumor samples of responders versus non-responders (p=0.04).
“We compared the tumor-associated immune infiltrates via multi-parameter immunohistochemistry (IHC) and observed a higher density of CD8+ T cells in baseline samples of R versus NR (p=0.04), consistent with prior reports (Fig. 4A and fig. S18) (18, 37).”
From Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients (2018) · cites this paper as [37]
Cancer cells can increase immune checkpoint molecules such as PD-L1, resulting in peripheral T cell exhaustion and inhibition of malignant cell apoptosis.
“Additionally, cancer cells can increase immune checkpoint molecules such as PD-L1, resulting in peripheral T cell exhaustion and the inhibition of malignant cell apoptosis [85].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [85]
PD-1 and CTLA-4 blockades are more effective in tumors infiltrated by T cells or with high mutation rates and thus more immunogenic prior to treatment.
“Indeed, as mentioned in the previous section, both PD-1 and CTLA-4 blockades are more effective in tumors that are infiltrated by T cells or that have high mutation rates and are therefore more immunogenic prior to treatment (86–88).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
An increase in CD8+ T cell proliferation within the tumor lesion and an increased frequency of Th9 cells in circulation were associated with treatment response.
“An increase in CD8+ T cell proliferation within the tumor lesion and an increased frequency of Th9 cells in the patients’ circulation were also associated with treatment response (88, 91, 92).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
Pre-treatment factors associated with improved treatment responses include high eosinophil and lymphocyte blood counts, abundance of CD8+ T cells infiltrating tumor or at tumor margin, and increased serum TGF-β levels in melanoma patients treated with anti-PD-1.
“Other pre-treatment immunological factors associated with improved treatment responses include high eosinophil and lymphocyte blood counts, an abundance of CD8+ T cells infiltrating the tumor or present at the tumor margin, and increased serum TGF-β levels in melanoma patients treated with anti-PD-1 (88, 91, 92, 109).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
Tumor-infiltrating lymphocytes are under active investigation as a biomarker for selecting patients for immune checkpoint therapy, although definitions and thresholds vary significantly.
“TILs are therefore under active investigation as a biomarker to guide selection of patients for treatment with ICT, although significant variability exists in definitions and thresholds (149, 150).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [149]
Presence of CD8+ T cells at tumor margins and within the tumor before checkpoint inhibitor treatment is associated with stronger response.
“The presence of CD8+ T cells at tumor margins and within the tumor prior to treatment with checkpoint inhibitors was associated with a stronger response to treatment (Tumeh et al., 2014).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
T cell abundance at the invasive tumor margin before treatment is associated with better response, and responding patients show increased T cell densities at the margin and within the tumor parenchyma after treatment.
“abundance of T cells at the invasive tumor margin prior to treatment was associated with a better response, whereas upon treatment, T cell densities were increased both at the margin and within the tumor parenchyma in responding patients”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
Higher baseline intratumoral CD8+ T cell density predicts favorable response to anti-PD-1 treatment in metastatic melanoma.
“In metastatic melanoma patients, a higher density of intratumoral CD8+ T cells at baseline was shown to predict favorable response to anti-PD-1 treatment”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
Some studies found that high TCR diversity in peripheral blood and tumors prior to immune checkpoint inhibitor therapy is predictive of effective treatment, while others found that increases in TCR clonality are a sign of effective therapy.
“some studies have found that high TCR diversity in peripheral blood and tumors prior to ICI therapy is predictive of effective treatment, others have pointed to ICI therapy-associated increases in TCR clonality, that is, enrichment of T cells with the same TCRs, as a sign of effective therapy (150, 157-161).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [150]
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“A first, relatively straightforward refinement is the subdivision of T cells based on their location at the tumor border or in the tumor parenchyma (9).”
Background
- Authors
- Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., West, A. N., Carmona, M., Kivork, C., Seja, E., Cherry, G., Gutierrez, A. J., Grogan, T. R., Mateus, C., Tomasic, G., Glaspy, J. A., Emerson, R. O., Robins, H., Pierce, R. H., Elashoff, D. A., Robert, C., & Ribas, A.
- Affiliations
- University of California, Los Angeles (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Inserm (FR)
- Adaptive Biotechnologies (United States) (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Tumeh, Paul C.
- Ribas, Antoni
- ORCID
- Venue
- Nature
- Published
- 2014-11-26
- Volume
- 515
- Issue
- 7528
- Pages
- 568-571
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4246418
- OpenAlex
- W2039123767
- Semantic Scholar
- 2c96ca62d538ff43fce01bc848fc018f6ae2b4a0
- Cited by
- 6,609
- References
- 24
- Citations by year
- 2026: 280 · 2025: 398 · 2024: 491 · 2023: 588 · 2022: 695 · 2021: 768 · 2020: 800 · 2019: 610 · 2018: 593 · 2017: 566 · 2016: 488 · 2015: 303 · 2014: 12 · 2013: 2 · 2012: 1
- FWCI
- 220.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Association for Cancer Research (SU2C-AACR-DT1012)
- Cancer Research Institute (SU2C-AACR-DT1012, CA16042)
- Melanoma Research Alliance (SU2C-AACR-DT1012)
- Adaptive Biotechnologies
- Institut Gustave-Roussy
- Sociedad Española de Oncología Médica
- National Institutes of Health (UL1TR000124, 5u54ca119347-03, P30 CA- 16042, SU2C-AACR-DT1012, CA16042)
- Stand Up To Cancer (SU2C-AACR-DT1012))
- National Cancer Institute (U54-CA119347, P01CA168585, P30-CA16042, R01CA170689, P30CA016042)
- National Institute of Allergy and Infectious Diseases (K08AI091663)
- National Center for Advancing Translational Sciences
- 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
- pembrolizumab, adaptive immune resistance, CD8+ T cells, PD-L1, PD-1/PD-L1 axis, metastatic melanoma, tumor-infiltrating lymphocytes, T cell receptor repertoire, predictive biomarkers, tumor regression, immune checkpoint inhibitors
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Immunotherapy, Male, Melanoma, Middle Aged, Models, Biological, Biomarkers, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Treatment Outcome, CD8-Positive T-Lymphocytes, Cell Proliferation, Adaptive Immunity, Programmed Cell Death 1 Receptor
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