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. -

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 46 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003977	RNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. RNA was sequenced using a capture based approach (exome capture, RNA access).	Illumina HiSeq 2500	348
EGAD00001004218	Tumor DNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. Normal DNA was extracted from matched PBMCs. Whole exome sequencing was performed. This is a subset of patients for which RNA sequencing is also provided (with more detailed phenotypic information).	Illumina HiSeq 2500	488

Publications	Citations
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T. Nature 554: 2018 544-548	3186
LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8<sup>+</sup> T cell tumor-infiltration impairing anti-PD1 therapy. Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, Cuartas I, Sala-Hojman A, Escudero L, Martínez-Ricarte F, Huber-Ruano I, Nuciforo P, Pedrosa L, Marques C, Braña I, Garralda E, Vieito M, Squatrito M, Pineda E, Graus F, Espejo C, Sahuquillo J, Tabernero J, Seoane J. Nat Commun 10: 2019 2416	133
Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Litchfield K, Reading JL, Lim EL, Xu H, Liu P, Al-Bakir M, Wong YNS, Rowan A, Funt SA, Merghoub T, Perkins D, Lauss M, Svane IM, Jönsson G, Herrero J, Larkin J, Quezada SA, Hellmann MD, Turajlic S, Swanton C. Nat Commun 11: 2020 3800	62
Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer. Ahn SG, Kim SK, Shepherd JH, Cha YJ, Bae SJ, Kim C, Jeong J, Perou CM. Breast Cancer Res Treat 188: 2021 165-178	17
Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade. Banchereau R, Chitre AS, Scherl A, Wu TD, Patil NS, de Almeida P, Kadel Iii EE, Madireddi S, Au-Yeung A, Takahashi C, Chen YJ, Modrusan Z, McBride J, Nersesian R, El-Gabry EA, Robida MD, Hung JC, Kowanetz M, Zou W, McCleland M, Caplazi P, Eshgi ST, Koeppen H, Hegde PS, Mellman I, Mathews WR, Powles T, Mariathasan S, Grogan J, O'Gorman WE. J Immunother Cancer 9: 2021 e002231	84
Transcriptomic signatures of tumors undergoing T cell attack. Gokuldass A, Schina A, Lauss M, Harbst K, Chamberlain CA, Draghi A, Westergaard MCW, Nielsen M, Papp K, Sztupinszki Z, Csabai I, Svane IM, Szallasi Z, Jönsson G, Donia M. Cancer Immunol Immunother 71: 2022 553-563	6
Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers. McGrail DJ, Pilié PG, Dai H, Lam TNA, Liang Y, Voorwerk L, Kok M, Zhang XH, Rosen JM, Heimberger AB, Peterson CB, Jonasch E, Lin SY. Sci Transl Med 13: 2021 eabe6201	20
<i>ACSL4</i> Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer. Luo W, Wang J, Dai X, Zhang H, Qu Y, Xiao W, Ye D, Zhu Y. Front Oncol 11: 2021 754845	7
Accounting for B-cell Behavior and Sampling Bias Predicts Anti-PD-L1 Response in Bladder Cancer. Dyugay IA, Lukyanov DK, Turchaninova MA, Serebrovskaya EO, Bryushkova EA, Zaretsky AR, Khalmurzaev O, Matveev VB, Shugay M, Shelyakin PV, Chudakov DM. Cancer Immunol Res 10: 2022 343-353	10
Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification. Chen Y, You S, Li J, Zhang Y, Kokaraki G, Epstein E, Carlson J, Huang WK, Haglund F. Front Immunol 12: 2021 788959	10
Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors. Nikolos F, Hayashi K, Hoi XP, Alonzo ME, Mo Q, Kasabyan A, Furuya H, Trepel J, Di Vizio D, Guarnerio J, Theodorescu D, Rosser C, Apolo A, Galsky M, Chan KS. Nat Commun 13: 2022 1487	26
Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes. Lee HJ, Song KH, Oh SJ, Kim S, Cho E, Kim J, Park YG, Lee KM, Yee C, Song SH, Chang S, Choi J, Jung ST, Kim TW. Nat Commun 13: 2022 2127	8
Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer. Zhang Q, Tan Y, Zhang J, Shi Y, Qi J, Zou D, Ci W. Front Immunol 13: 2022 782982	26
Prediction of the Immune Phenotypes of Bladder Cancer Patients for Precision Oncology. Cho H, Tong F, You S, Jung S, Kim WH, Kim J. IEEE Open J Eng Med Biol 3: 2022 47-57	1
Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review. Kovács SA, Győrffy B. J Transl Med 20: 2022 249	37
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Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients. Seitz RS, Hurwitz ME, Nielsen TJ, Bailey DB, Varga MG, Ring BZ, Metts CF, Schweitzer BL, McGregor K, Ross DT. J Transl Med 20: 2022 370	7
Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer. Zhu D, Jiang Y, Cao H, Yang J, Shu Y, Feng H, Yang X, Sun X, Shao M. Front Immunol 13: 2022 876195	13
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M7G-related molecular subtypes can predict the prognosis and correlate with immunotherapy and chemotherapy responses in bladder cancer patients. Li DX, Feng DC, Wang XM, Wu RC, Zhu WZ, Chen K, Han P. Eur J Med Res 28: 2023 55	21
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Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells. Qin G, Liu S, Liu J, Hu H, Yang L, Zhao Q, Li C, Zhang B, Zhang Y. Signal Transduct Target Ther 8: 2023 164	17
The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response. Dunker W, Zaver SA, Pineda JMB, Howard CJ, Bradley RK, Woodward JJ. JCI Insight 8: 2023 e167270	5
In situ tumour arrays reveal early environmental control of cancer immunity. Ortiz-Muñoz G, Brown M, Carbone CB, Pechuan-Jorge X, Rouilly V, Lindberg H, Ritter AT, Raghupathi G, Sun Q, Nicotra T, Mantri SR, Yang A, Doerr J, Nagarkar D, Darmanis S, Haley B, Mariathasan S, Wang Y, Gomez-Roca C, de Andrea CE, Spigel D, Wu T, Delamarre L, Schöneberg J, Modrusan Z, Price R, Turley SJ, Mellman I, Moussion C. Nature 618: 2023 827-833	18
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. Ferreiro-Pantín M, Anido-Herranz U, Betancor YZ, Cebey-López V, León-Mateos L, García-González J, García-Acuña SM, Fernández-Díaz N, Tubio JMC, López-López R, Ruiz-Bañobre J. ESMO Open 8: 2023 101611	6
Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors. Castiglioni A, Yang Y, Williams K, Gogineni A, Lane RS, Wang AW, Shyer JA, Zhang Z, Mittman S, Gutierrez A, Astarita JL, Thai M, Hung J, Yang YA, Pourmohamad T, Himmels P, De Simone M, Elstrott J, Capietto AH, Cubas R, Modrusan Z, Sandoval W, Ziai J, Gould SE, Fu W, Wang Y, Koerber JT, Sanjabi S, Mellman I, Turley SJ, Müller S. Nat Commun 14: 2023 4703	31
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Spatial transformation of multi-omics data unlocks novel insights into cancer biology. Sokač M, Kjær A, Dyrskjøt L, Haibe-Kains B, Jwl Aerts H, Birkbak NJ. Elife 12: 2023 RP87133	2
Adhesion-regulating molecule 1 (ADRM1) can be a potential biomarker and target for bladder cancer. Yu QX, Wang JC, Liu JF, Ye LX, Guo YQ, Zheng HH. Sci Rep 13: 2023 14803	8
Integrating Single-Cell RNA-Seq and Bulk RNA-Seq Data to Explore the Key Role of Fatty Acid Metabolism in Breast Cancer. Chen Y, Wu W, Jin C, Cui J, Diao Y, Wang R, Xu R, Yao Z, Li X. Int J Mol Sci 24: 2023 13209	2
Multi-omics indicators of long-term survival benefits after immune checkpoint inhibitor therapy. Zhao J, Dong Y, Bai H, Bai F, Yan X, Duan J, Wan R, Xu J, Fei K, Wang J, Wang Z. Cell Rep Methods 3: 2023 100596	5
Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer. Kim K, Kim H, Shin I, Noh SJ, Kim JY, Suh KJ, Kim YN, Lee JY, Cho DY, Kim SH, Kim JH, Lee SH, Choi JK. Sci Rep 13: 2023 22482	4
Interferon-stimulated neutrophils as a predictor of immunotherapy response. Benguigui M, Cooper TJ, Kalkar P, Schif-Zuck S, Halaban R, Bacchiocchi A, Kamer I, Deo A, Manobla B, Menachem R, Haj-Shomaly J, Vorontsova A, Raviv Z, Buxbaum C, Christopoulos P, Bar J, Lotem M, Sznol M, Ariel A, Shen-Orr SS, Shaked Y. Cancer Cell 42: 2024 253-265.e12	45
T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis. Fan Z, Liu Y, Li C, Jiang Y, Wang N, Wang M, Li C, Diao Y, Qiu W, Zhu X, Wang G, Cai S, Yang T, Lv G. iScience 27: 2024 108701	7
A Multi-Gene Signature of Non-Muscle-Invasive Bladder Cancer Identifies Patients Who Respond to Immunotherapies Including Bacillus Calmette-Guérin and Immune Checkpoint Inhibitors. Baek SW, Leem SH. Int J Mol Sci 25: 2024 3800	1
An endothelial-related prognostic index for bladder cancer patients. Li DX, Wu RC, Wang J, Yu QX, Tuo ZT, Ye LX, Feng DC, Deng S. Discov Oncol 15: 2024 128	2
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DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers. Pineda JMB, Bradley RK. Elife 12: 2024 RP89017	4
Comprehensive pan-cancer analysis of mitochondrial outer membrane permeabilisation activity reveals positive immunomodulation and assists in identifying potential therapeutic targets for immunotherapy resistance. Chen Q, Gao F, Wu J, Zhang K, Du T, Chen Y, Cai R, Zhao D, Deng R, Tang J. Clin Transl Med 14: 2024 e1735	2
MOSBY enables multi-omic inference and spatial biomarker discovery from whole slide images. Şenbabaoğlu Y, Prabhakar V, Khormali A, Eastham J, Liu E, Warner E, Nabet B, Srivastava M, Ballinger M, Liu K. Sci Rep 14: 2024 18271	1
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Unveiling the pan-cancer landscape of S100A16: A comprehensive analysis of prognostic significance, drug sensitivity, and immunomodulatory roles. Shang S, Hu L, Wu C, Wu J, Chen M, Zhu G, Xu WY, Zhang Y, Sun G, Wei Z. Medicine (Baltimore) 103: 2024 e39998	0
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Predicting immunotherapy response of advanced bladder cancer through a meta-analysis of six independent cohorts. Boll LM, Vázquez Montes de Oca S, Camarena ME, Castelo R, Bellmunt J, Perera-Bel J, Albà MM. Nat Commun 16: 2025 1213	0
Targeting tumor-intrinsic S100 calcium-binding protein A1 augments antitumor immunity and potentiates immunotherapy efficacy. Guo Y, Wan R, Duan J, Yuan L, Wang Z, Zhong J, Zhang X, Ma Z, Bai H, Wang J. Signal Transduct Target Ther 10: 2025 99	0