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 34 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	2392
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	93
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	45
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	10
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	59
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	15
<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	5
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	6
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	6
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	12
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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	16
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Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review. Kovács SA, Győrffy B. J Transl Med 20: 2022 249	21
Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Luoma AM, Suo S, Wang Y, Gunasti L, Porter CBM, Nabilsi N, Tadros J, Ferretti AP, Liao S, Gurer C, Chen YH, Criscitiello S, Ricker CA, Dionne D, Rozenblatt-Rosen O, Uppaluri R, Haddad RI, Ashenberg O, Regev A, Van Allen EM, MacBeath G, Schoenfeld JD, Wucherpfennig KW. Cell 185: 2022 2918-2935.e29	76
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	3
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	11
Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy. Subramanian M, Kabir AU, Barisas D, Krchma K, Choi K. Cell Rep Med 4: 2023 100896	5
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	4
The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. Ahrenfeldt J, Christensen DS, Østergaard AB, Kisistók J, Sokač M, Birkbak NJ. PLoS One 18: 2023 e0281375	1
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	5
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	1
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	4
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	0
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	0
Intratumoral T-cell and B-cell receptor architecture associates with distinct immune tumor microenvironment features and clinical outcomes of anti-PD-1/L1 immunotherapy. Schina A, Sztupinszki Z, Marie Svane I, Szallasi Z, Jönsson G, Donia M. J Immunother Cancer 11: 2023 e006941	1
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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	0
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	0
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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	0
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	1
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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	0