TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Open accessAbstract
Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Higher TGF-β signaling within the tumor microenvironment is associated with worse overall survival and with resistance to blockade of PD-L1 or PD-1.
“increased TGF-β signaling in the TME correlates with poor overall survival and resistance to immunotherapeutic blockade of PD-L1 or its receptor, PD-121–24.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
Recent results highlight the role of increased TGF-β signaling in intrinsic resistance to checkpoint blockade therapy.
“Recent results in fact highlight the role of increased TGF-β signaling in intrinsic resistance to checkpoint blockade therapy21,23,38,71,145.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
TGF-β signaling in CAFs is increasingly seen as a determinant of resistance to immunotherapy.
“TGF-β signaling in CAFs is increasingly seen as a determinant of resistance to immunotherapy21,23,77.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
CAFs do express TGF-β3, as do some mesenchymal tumors.
“However, CAFs do express TGF-β3, as do some mesenchymal tumors21,23,41,69.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
TGF-β released and activated by cancer cells, stromal fibroblasts, and/or immune cells dampens anti-tumor immunity and responses to immunotherapeutics through direct and indirect mechanisms.
“An underlying and predominant rationale focuses on the ability of TGF-β released and activated by cancer cells, stromal fibroblasts and/or immune cells to dampen anti-tumor immunity and responses to immunotherapeutics through direct and indirect mechanisms21,23,71,145,353,354.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
Galunisertib, neutralizing anti-TGF-β antibodies, an antibody preventing TGF-β1 activation, and anti-integrin β8 antibodies enhance the anti-tumor efficacy of PD-1/PD-L1 blockade.
“Galunisertib23,353, neutralizing anti-TGF-β antibodies21,145, an antibody that prevents TGF-β1 activation71 and anti-integrin β8 antibodies that prevent TGF-β activation85,319 were shown to enhance the anti-tumor efficacy of PD-1/PD-L1 blockade.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
Treatments combining TGF-β inhibition with immune checkpoint inhibition are likely to increase therapeutic efficacy.
“treatments that combine TGF-β inhibition with immune checkpoint inhibition are likely to increase therapeutic efficacy21,23,71,145,346,362.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
Melanomas and urothelial carcinomas intrinsically resistant to anti-PD-1/PD-L1 therapy show elevated TGF-β signaling, particularly in the stromal compartment of immune-excluded tumors.
“Melanomas and urothelial carcinomas that are intrinsically resistant to anti-PD-1/PD-L1 therapy show elevated TGF-β signaling, particularly in the stromal compartment of immune excluded tumors21,77,228,361.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
In murine cancer models, anti-PD-1 or anti-PD-L1 enhance the anti-tumor responses of anti-TGF-β, and vice versa, resulting in potent and durable cytotoxic T cell responses that can clear large aggressive primary tumors and suppress metastasis.
“Depending on the model and experimental design, anti-PD-1 or anti-PD-L1 enhance the anti-tumor responses of anti-TGF-β, and vice versa, and result in potent and durable cytotoxic T cell responses that can clear even large and aggressive primary tumors, and suppress cancer metastasis21,23,145,346,353,362.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
TGF-β, CTLA-4, and PD-L1/PD-1 signaling act as parallel immunosuppressive pathways that repress cytotoxic T cell, NK cell, and macrophage activities through distinct mechanisms.
“Considering that TGF-β, CTLA-4 and PD-L1/PD-1 signaling act as parallel immunosuppressive pathways that repress cytotoxic T cell, NK cell and macrophage activities through distinct mechanisms”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [21]
Preclinical data suggest that TGFb blockers may reduce immune-cell exclusion from the tumor microenvironment, enabling responsiveness to PD-1 or PD-L1 checkpoint inhibitors.
“but also to limit the exclusion of immune cells from the TME, hence enabling (at least some) responsiveness to ICIs targeting PD-1 or PD-L1”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Mariathasan et al., 2018
Hyperactivated TGF-β signaling was associated with poor response to α-PD-1/PD-L1, and blocking TGF-β significantly improved the efficacy of α-PD-1/PD-L1.
“Hyperactivated TGF-β signaling was associated with the poor response to α-PD-1/PD-L1, and blocking TGF-β significantly improved the efficacy of α-PD-1/PD-L1 [299–302].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [300]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 36 · Cited by 5,400
Research works printed but not linked: 1
- [26]Dobson AJ Barnett AG An Introduction to Generalized Linear Models, Third Edition Chapman & Hall/CRC Press 2008
- Authors
- Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., Jhunjhunwala, S., Banchereau, R., Yang, Y., Guan, Y., Chalouni, C., Ziai, J., Şenbabaoğlu, Y., Santoro, S., Sheinson, D., Hung, J., Giltnane, J. M., Pierce, A. A., Mesh, K., Lianoglou, S., Riegler, J., Carano, R. A. D., Eriksson, P., Höglund, M., Somarriba, L., Halligan, D. L., van der Heijden, M. S., Loriot, Y., Rosenberg, J. E., Fong, L., Mellman, I., Chen, D. S., Green, M., Derleth, C., Fine, G. D., Hegde, P. S., Bourgon, R., & Powles, T.
- Affiliations
- Genentech (US)
- Lund University (SE)
- Fios Genomics (United Kingdom) (GB)
- Université Paris-Sud (FR)
- Memorial Sloan Kettering Cancer Center (US)
- University of California, San Francisco (US)
- Queen Mary University of London (GB)
- Corresponding author
- Mariathasan, Sanjeev
- Turley, Shannon J.
- Bourgon, Richard
- ORCID
- Mariathasan, Sanjeev
- Turley, Shannon J.
- Nickles, Dorothee
- Castiglioni, Alessandra
- Yuen, Kobe
- Wang, Yulei
- Koeppen, Hartmut
- Astarita, Jillian L.
- Cubas, Rafael
- Jhunjhunwala, Suchit
- Banchereau, Romain
- Guan, Yinghui
- Chalouni, Cecile
- Ziai, James
- Şenbabaoğlu, Yasin
- Hung, Jeffrey
- Giltnane, Jennifer M.
- Pierce, Andrew A.
- Lianoglou, Steve
- Riegler, Johannes
- Carano, Richard A. D.
- Eriksson, Pontus
- Höglund, Mattias
- Halligan, Daniel L.
- Loriot, Yohann
- Rosenberg, Jonathan E.
- Fong, Lawrence
- Mellman, Ira
- Chen, Daniel S.
- Bourgon, Richard
- Powles, Thomas
- Venue
- Nature
- Published
- 2018-02
- Volume
- 554
- Issue
- 7693
- Pages
- 544-548
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6028240
- OpenAlex
- W2785803176
- Cited by
- 5,400
- References
- 36
- Citations by year
- 2026: 658 · 2025: 592 · 2024: 790 · 2023: 831 · 2022: 961 · 2021: 686 · 2020: 457 · 2019: 282 · 2018: 138 · 2017: 1 · 2012: 1
- FWCI
- 148.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Cancer Institute (R01CA194511, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TGF-beta signaling, PD-L1 blockade, immune checkpoint inhibitors, atezolizumab, metastatic urothelial carcinoma, immune exclusion, CD8+ T cells, tumor microenvironment, cancer-associated fibroblasts, neoantigen burden, tumor mutational burden, T-cell exclusion, TGF-beta blockade
- MeSH terms
- Animals, Antibodies, Antibodies, Monoclonal, Antigens, Neoplasm, Collagen, Disease Models, Animal, Fibroblasts, Humans, Immunotherapy, Mutation, Neoplasm Metastasis, Phenotype, Urologic Neoplasms, Cohort Studies, Signal Transduction, Transforming Growth Factor beta, Treatment Outcome, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Urothelium, Mice, Tumor Microenvironment, Cell Cycle Checkpoints, B7-H1 Antigen, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
