- •CXCL13 expression predicts survival for advanced-stage MIBC treated with ICI.
- •CXCL13 expression correlates with the presence of TLS in TCGA tumours.
- •Ba/Sq and stroma-rich subtypes have higher CXCL13 expression and harbour more TLS.
- •We suggest CXCL13 as a predictive biomarker for ICI response in bladder cancer.
Immune checkpoint inhibitors (ICIs) have proved to be an effective treatment for up to 40% of muscle-invasive bladder cancer (MIBC), but there is still a need for better performing biomarkers allowing to improve prediction of response to ICI. Response to immunotherapy in soft-tissue sarcoma, melanoma and renal cell carcinoma have been recently linked to the presence of tertiary lymphoid structures (TLS) in the tumour. TLS are organised aggregates of T, B and dendritic cells, participating in adaptive antitumor immune response. The chemokine CXCL13 is involved in the formation of TLS, and is reported as a reliable transcriptomic marker of TLS.
In this study, we sought to assess whether CXCL13 transcript expression can be a prognostic biomarker for ICI-treated MIBC patients and also investigated whether it can serve a biomarker of TLS in MIBC.
We analysed transcriptomic data from three publicly available MIBC cohorts and evaluated pathological slides from the TCGA-BLCA cohort for TLS presence and stage of maturation.
We showed that CXCL13 was independently associated with both prolonged survival (HR = 0.8, 95% CI [0.68–0.94]) and objective response (p < 0.0001) in patients treated with ICI, at the difference of others immunological signatures. However, it was not a predictor for non–ICI-treated MIBC, suggesting a predictive effect of ICI efficacy. Finally, we validated that CXCL13 expression was correlated with tumour TLS in TCGA data set (p < 0.001), and can serve as a marker of TLS in bladder cancer.
These results support that CXCL13 expression, as a surrogate for tumour TLS, is a relevant candidate predictive biomarker of response to ICI for patients with advanced-stage bladder cancer.
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- TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.Nature. 2018; 554: 544-548https://doi.org/10.1038/nature25501
- Impact of molecular subtyping and immune infiltration on pathological response and outcome following neoadjuvant pembrolizumab in muscle-invasive bladder cancer.Eur Urol. 2020; : 1-10https://doi.org/10.1016/j.eururo.2020.02.028
- Tertiary lymphoid structures in the era of cancer immunotherapy.Nat Rev Canc. 2019; 19: 307-325https://doi.org/10.1038/s41568-019-0144-6
- Tertiary lymphoid structures improve immunotherapy and survival in melanoma.Nature. 2020; 577https://doi.org/10.1038/s41586-019-1914-8
- B cells are associated with survival and immunotherapy response in sarcoma.Nature. 2020; 577: 556-560https://doi.org/10.1038/s41586-019-1906-8
- B cells and tertiary lymphoid structures promote immunotherapy response.Nature. 2020; 577: 549-555https://doi.org/10.1038/s41586-019-1922-8
- Tertiary lymphoid structures associate with tumour stage in urothelial bladder cancer.Bladder Cancer. 2017; 3: 259-267https://doi.org/10.3233/BLC-170120
- Comprehensive molecular characterization of muscle-invasive bladder cancer.Cell. 2017; 171 (e25): 540-556https://doi.org/10.1016/J.CELL.2017.09.007
- Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy.Eur Urol. 2017; 72: 544-554https://doi.org/10.1016/j.eururo.2017.03.030
- ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC.Sci Transl Med. 2020; 12https://doi.org/10.1126/scitranslmed.abc4220
- Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma.J Hepatol. 2019; 70: 58-65https://doi.org/10.1016/j.jhep.2018.09.003
- A consensus molecular classification of muscle-invasive bladder cancer.Eur Urol. 2020; 77https://doi.org/10.1016/j.eururo.2019.09.006
- Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.Nat Med. 2019; 25: 1706-1714https://doi.org/10.1038/s41591-019-0628-7
- Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells.Immunity. 2007; 26: 643-654https://doi.org/10.1016/j.immuni.2007.04.009
- The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes.Canc Cell. 2020; 38 (e8): 685-700https://doi.org/10.1016/j.ccell.2020.09.001
- Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+T cells.Canc Res. 2014; 74: 705-715https://doi.org/10.1158/0008-5472.CAN-13-1342
- Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T- cell responses, and superior prognosis in ovarian cancer.Clin Canc Res. 2016; 22: 3005-3015https://doi.org/10.1158/1078-0432.CCR-15-2762
- Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling.Am J Pathol. 2011; 179: 37-45https://doi.org/10.1016/j.ajpath.2011.03.007
- 12-chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy?.Sci Rep. 2012; 2: 1-6https://doi.org/10.1038/srep00765
- Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients.OncoImmunology. 2016; 5: 2https://doi.org/10.1080/2162402X.2015.1054598
- The high level of tertiary lymphoid structure is correlated with superior survival in patients with advanced gastric cancer.Front Oncol. 2020; 10: 980https://doi.org/10.3389/fonc.2020.00980
- Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer.Mod Pathol. 2017; 30: 1204-1212https://doi.org/10.1038/modpathol.2017.43
- Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.Nat Med. 2020; 26https://doi.org/10.1038/s41591-020-1086-y
- Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.Nat Med. 2020; https://doi.org/10.1038/s41591-020-1085-z
- Early hepatic lesions display immature tertiary lymphoid structures and show elevated expression of immune inhibitory and immunosuppressive molecules.Clin Canc Res. 2020; 26 (clincanres.2929.2019)https://doi.org/10.1158/1078-0432.ccr-19-2929
Published online: March 18, 2021
Accepted: January 29, 2021
Received in revised form: December 22, 2020
Received: October 23, 2020
© 2021 Elsevier Ltd. All rights reserved.
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- CXCL13 shapes tertiary lymphoid structures and promotes response to immunotherapy in bladder cancerEuropean Journal of CancerVol. 151
- PreviewThe CXC-chemokine ligand 13 (CXCL13) was identified 20 years ago and described as a key regulator of B cells migration to secondary lymphoid organs (Ansel et al. Nature 2000, Gunn et al. Nature 1998). The main function of CXCL13 is to control the recruitment and organization of B cells within lymphoid follicles. CXCL13 selectively binds to the chemokine receptor CXCR5 (CD185), which is normally expressed on mature B cells and a subset of CD4+ T cells called follicular helper T (Tfh) cells and follicular dendritic cells.