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TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

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Dataset ID Description Technology Samples
EGAD00001003977 Illumina HiSeq 2500 348
EGAD00001004218 Illumina HiSeq 2500 488
Publications Citations
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
Nature 554: 2018 544-548
2659
LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8<sup>+</sup> T cell tumor-infiltration impairing anti-PD1 therapy.
Nat Commun 10: 2019 2416
106
Escape from nonsense-mediated decay associates with anti-tumor immunogenicity.
Nat Commun 11: 2020 3800
55
Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer.
Breast Cancer Res Treat 188: 2021 165-178
11
Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade.
J Immunother Cancer 9: 2021 e002231
65
Transcriptomic signatures of tumors undergoing T cell attack.
Cancer Immunol Immunother 71: 2022 553-563
5
Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers.
Sci Transl Med 13: 2021 eabe6201
19
<i>ACSL4</i> Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer.
Front Oncol 11: 2021 754845
5
Accounting for B-cell Behavior and Sampling Bias Predicts Anti-PD-L1 Response in Bladder Cancer.
Cancer Immunol Res 10: 2022 343-353
6
Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification.
Front Immunol 12: 2021 788959
7
Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors.
Nat Commun 13: 2022 1487
15
Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes.
Nat Commun 13: 2022 2127
5
Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer.
Front Immunol 13: 2022 782982
20
Prediction of the Immune Phenotypes of Bladder Cancer Patients for Precision Oncology.
IEEE Open J Eng Med Biol 3: 2022 47-57
1
Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review.
J Transl Med 20: 2022 249
33
Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.
Cell 185: 2022 2918-2935.e29
117
Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients.
J Transl Med 20: 2022 370
3
Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer.
Front Immunol 13: 2022 876195
13
Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy.
Cell Rep Med 4: 2023 100896
12
M7G-related molecular subtypes can predict the prognosis and correlate with immunotherapy and chemotherapy responses in bladder cancer patients.
Eur J Med Res 28: 2023 55
12
The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy.
PLoS One 18: 2023 e0281375
3
Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells.
Signal Transduct Target Ther 8: 2023 164
7
The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.
JCI Insight 8: 2023 e167270
2
In situ tumour arrays reveal early environmental control of cancer immunity.
Nature 618: 2023 827-833
9
Clinical, molecular, and immune correlates of the Immunotherapy Response Score in patients with advanced urothelial carcinoma under atezolizumab monotherapy: analysis of the phase II IMvigor210 trial.
ESMO Open 8: 2023 101611
3
Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors.
Nat Commun 14: 2023 4703
11
Intratumoral T-cell and B-cell receptor architecture associates with distinct immune tumor microenvironment features and clinical outcomes of anti-PD-1/L1 immunotherapy.
J Immunother Cancer 11: 2023 e006941
3
Spatial transformation of multi-omics data unlocks novel insights into cancer biology.
Elife 12: 2023 RP87133
1
Adhesion-regulating molecule 1 (ADRM1) can be a potential biomarker and target for bladder cancer.
Sci Rep 13: 2023 14803
4
Integrating Single-Cell RNA-Seq and Bulk RNA-Seq Data to Explore the Key Role of Fatty Acid Metabolism in Breast Cancer.
Int J Mol Sci 24: 2023 13209
0
Multi-omics indicators of long-term survival benefits after immune checkpoint inhibitor therapy.
Cell Rep Methods 3: 2023 100596
3
Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer.
Sci Rep 13: 2023 22482
1
Interferon-stimulated neutrophils as a predictor of immunotherapy response.
Cancer Cell 42: 2024 253-265.e12
11
T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis.
iScience 27: 2024 108701
2
A Multi-Gene Signature of Non-Muscle-Invasive Bladder Cancer Identifies Patients Who Respond to Immunotherapies Including Bacillus Calmette-Guérin and Immune Checkpoint Inhibitors.
Int J Mol Sci 25: 2024 3800
0
An endothelial-related prognostic index for bladder cancer patients.
Discov Oncol 15: 2024 128
1
DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.
Elife 12: 2024 RP89017
3
Comprehensive pan-cancer analysis of mitochondrial outer membrane permeabilisation activity reveals positive immunomodulation and assists in identifying potential therapeutic targets for immunotherapy resistance.
Clin Transl Med 14: 2024 e1735
0
MOSBY enables multi-omic inference and spatial biomarker discovery from whole slide images.
Sci Rep 14: 2024 18271
0
Multimodal analysis unveils tumor microenvironment heterogeneity linked to immune activity and evasion.
iScience 27: 2024 110529
0
Unveiling the pan-cancer landscape of S100A16: A comprehensive analysis of prognostic significance, drug sensitivity, and immunomodulatory roles.
Medicine (Baltimore) 103: 2024 e39998
0