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Open Access 01-04-2024 | Cytostatic Therapy | Research

Integrating molecular subtype and CD8⁺ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer

Authors: Bingyu Li, Kaifeng Jin, Zhaopei Liu, Xiaohe Su, Ziyue Xu, Ge Liu, Jingtong Xu, Hailong Liu, Yuan Chang, Yiwei Wang, Yu Zhu, Zewei Wang, Le Xu, Weijuan Zhang

Published in: Cancer Immunology, Immunotherapy | Issue 4/2024

Abstract

Background

Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8⁺ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8⁺ T cells infiltration in MIBC.

Methods

This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8⁺ T cells and probed into the clinical implications of these subgroups in MIBC.

Results

Among patients with Luminal-CD8⁺T^high tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8⁺T^low displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8⁺T^low subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8⁺T^high counterparts exhibited a heightened responsiveness to chemotherapy.

Conclusions

We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660CrossRefPubMed

Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y (2017) Bladder cancer. Nat Rev Dis Primers 3:17022. https://doi.org/10.1038/nrdp.2017.22CrossRefPubMed

Cathomas R, Lorch A, Bruins HM et al (2022) The 2021 updated european association of urology guidelines on metastatic urothelial carcinoma. Eur Urol 81:95–103. https://doi.org/10.1016/j.eururo.2021.09.026CrossRefPubMed

Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England) 387:1909–1920. https://doi.org/10.1016/s0140-6736(16)00561-4CrossRefPubMed

Damrauer JS, Hoadley KA, Chism DD et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111:3110–3115. https://doi.org/10.1073/pnas.1318376111CrossRefPubMedPubMedCentral

Choi W, Porten S, Kim S et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165. https://doi.org/10.1016/j.ccr.2014.01.009CrossRefPubMedPubMedCentral

Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322. https://doi.org/10.1038/nature12965CrossRef

Balar AV, Galsky MD, Rosenberg JE et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (London, England) 389:67–76. https://doi.org/10.1016/s0140-6736(16)32455-2CrossRefPubMed

Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213. https://doi.org/10.1056/NEJMoa020177CrossRefPubMed

10.

Cho Y, Miyamoto M, Kato K et al (2003) CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Can Res 63:1555–1559

11.

Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Can Res 58:3491–3494

12.

Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160. https://doi.org/10.1038/nrclinonc.2010.223CrossRefPubMed

13.

Rahim MK, Okholm TLH, Jones KB et al (2023) Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell 186:1127–43.e18. https://doi.org/10.1016/j.cell.2023.02.021CrossRefPubMedPubMedCentral

14.

Jin K, Yu Y, Zeng H et al (2022) CD103(+)CD8(+) tissue-resident memory T cell infiltration predicts clinical outcome and adjuvant therapeutic benefit in muscle-invasive bladder cancer. Br J Cancer 126:1581–1588. https://doi.org/10.1038/s41416-022-01725-6CrossRefPubMedPubMedCentral

15.

Liu Z, Zhou Q, Wang Z et al (2020) Intratumoral TIGIT(+) CD8(+) T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-000978CrossRefPubMedPubMedCentral

16.

Huang Q, Zhou Q, Zhang H et al (2020) Identification and validation of an excellent prognosis subtype of muscle-invasive bladder cancer patients with intratumoral CXCR5(+) CD8(+) T cell abundance. Oncoimmunology 9:1810489. https://doi.org/10.1080/2162402x.2020.1810489CrossRefPubMedPubMedCentral

17.

Witjes JA, Bruins HM, Cathomas R et al (2021) European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol 79:82–104. https://doi.org/10.1016/j.eururo.2020.03.055CrossRefPubMed

18.

Bagaev A, Kotlov N, Nomie K et al (2021) Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 39:845–65.e7. https://doi.org/10.1016/j.ccell.2021.04.014CrossRefPubMed

19.

Wherry EJ, Ha SJ, Kaech SM et al (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–684. https://doi.org/10.1016/j.immuni.2007.09.006CrossRefPubMed

20.

Ayers M, Lunceford J, Nebozhyn M et al (2017) IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940. https://doi.org/10.1172/jci91190CrossRefPubMedPubMedCentral

21.

Mariathasan S, Turley SJ, Nickles D et al (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–548. https://doi.org/10.1038/nature25501CrossRefPubMedPubMedCentral

22.

Barbie DA, Tamayo P, Boehm JS et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462:108–112. https://doi.org/10.1038/nature08460CrossRefPubMedPubMedCentral

23.

Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G (2011) GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 12:41. https://doi.org/10.1186/gb-2011-12-4-r41CrossRef

24.

Zeng H, Liu Z, Wang Z et al (2020) Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses. Int J Cancer 146:542–552. https://doi.org/10.1002/ijc.32715CrossRefPubMed

25.

Dadhania V, Zhang M, Zhang L et al (2016) Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use. EBioMedicine 12:105–117. https://doi.org/10.1016/j.ebiom.2016.08.036CrossRefPubMedPubMedCentral

26.

Xu Y, Zeng H, Jin K, Liu Z, Zhu Y, Xu L, Wang Z, Chang Y, Xu J (2022) Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer. J Immunother Cancer. https://doi.org/10.1136/jitc-2021-003416CrossRefPubMedPubMedCentral

27.

Powles T, Durán I, van der Heijden MS et al (2018) Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet (London, England) 391:748–757. https://doi.org/10.1016/s0140-6736(17)33297-xCrossRefPubMed

28.

Shi R, Wang X, Wu Y et al (2022) APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases. Theranostics 12:4181–4199. https://doi.org/10.7150/thno.73235CrossRefPubMedPubMedCentral

29.

Goldstein JT, Berger AC, Shih J, Duke FF, Furst L, Kwiatkowski DJ, Cherniack AD, Meyerson M, Strathdee CA (2017) Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer. Can Res 77:6987–6998. https://doi.org/10.1158/0008-5472.Can-17-1701CrossRef

30.

Rosenberg JE, O’Donnell PH, Balar AV et al (2019) Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 37:2592–2600. https://doi.org/10.1200/jco.19.01140CrossRefPubMedPubMedCentral

31.

Tagawa ST, Balar AV, Petrylak DP et al (2021) TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 39:2474–2485. https://doi.org/10.1200/jco.20.03489CrossRefPubMedPubMedCentral

32.

Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736. https://doi.org/10.1016/j.ccr.2012.09.022CrossRefPubMedPubMedCentral

33.

Powles T, Kockx M, Rodriguez-Vida A et al (2019) Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 25:1706–1714. https://doi.org/10.1038/s41591-019-0628-7CrossRefPubMed

34.

van Dijk N, Gil-Jimenez A, Silina K et al (2020) Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med 26:1839–1844. https://doi.org/10.1038/s41591-020-1085-zCrossRefPubMed

35.

Rozeman EA, Hoefsmit EP, Reijers ILM et al (2021) Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med 27:256–263. https://doi.org/10.1038/s41591-020-01211-7CrossRefPubMed

36.

Ma Z, Li X, Mao Y, Wei C, Huang Z, Li G, Yin J, Liang X, Liu Z (2022) Interferon-dependent SLC14A1(+) cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell 40:1550–65.e7. https://doi.org/10.1016/j.ccell.2022.11.005CrossRefPubMed

37.

Spaan I, Raymakers RA, van de Stolpe A, Peperzak V (2018) Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential. J Hematol Oncol 11:67. https://doi.org/10.1186/s13045-018-0615-3CrossRefPubMedPubMedCentral

38.

Zhang M, Weng W, Zhang Q et al (2018) The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol 11:113. https://doi.org/10.1186/s13045-018-0656-7CrossRefPubMedPubMedCentral

39.

Zhang J, Cai H, Sun L, Zhan P, Chen M, Zhang F, Ran Y, Wan J (2018) LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients. J Exp Clin Cancer Res CR 37:225. https://doi.org/10.1186/s13046-018-0864-6CrossRefPubMed

40.

Stewart DJ (2014) Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djt356CrossRefPubMedPubMedCentral

41.

Álvarez-Fernández M, Malumbres M (2020) Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell 37:514–529. https://doi.org/10.1016/j.ccell.2020.03.010CrossRefPubMed

42.

Ingham M, Schwartz GK (2017) Cell-cycle therapeutics come of age. J Clin Oncol 35:2949–2959. https://doi.org/10.1200/jco.2016.69.0032CrossRefPubMedPubMedCentral

Title: Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer
Authors: Bingyu Li
Kaifeng Jin
Zhaopei Liu
Xiaohe Su
Ziyue Xu
Ge Liu
Jingtong Xu
Hailong Liu
Yuan Chang
Yiwei Wang
Yu Zhu
Zewei Wang
Le Xu
Weijuan Zhang
Publication date: 01-04-2024
Publisher: Springer Berlin Heidelberg
Keyword: Cytostatic Therapy
Published in: Cancer Immunology, Immunotherapy / Issue 4/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-024-03651-3

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