Prognostic Significance of the CXCL11/CXCL9/CD163 Immune Signature in Triple-Negative Breast Cancer: A Bioinformatics and Survival Analysis CXCL11/CXCL9 Prognostic Value
Abstract
Background: Triple-negative breast cancer remains a clinical challenge due to its aggressive nature and poor prognosis. Although it is characterized by a significant immune infiltration, this infiltration often fails to provide protection, requiring precise identification of the genetic hubs driving this failure. This study aimed to identify an immune gene signature associated with favorable prognosis in TNBC using a bioinformatics approach.
Methods: Gene expression data were extracted from the GSE53752 dataset (GEO), GPL13607, includes 51 TNBC tumors and 25 normal tissues, Differential expression analysis was performed. Followed by functional enrichment and protein interaction network (STRING) analysis to identify key immune pathways. Relapse-free survival (RFS) was evaluated for individual genes and for the combined CXCL9/CXCL11/CD163) signature by KM_ Plotter (n = 533) Results: Enrichment analysis demonstrated the dominance of chemokine signaling pathways and the inflammatory response. STRING analysis revealed a robust network centered on chemokines CXCL9, CXCL11, and the macrophage marker CD163. Multivariate Cox regression analysis confirmed that the CXCL9/CXCL11/CD163 signature is an independent predictor significantly associated with a reduced relapse-free survival rate (HR = 0.45; P = 2.3 × 10, indicating a twofold
increase in risk in patients with high signature activation Notably, traditional clinical factors did not reach statistical significance.
Conclusion: In conclusion the CXCL11/CXCL9/CD163 axis represents a strong, independent positive prognostic factor in TNBC. These findings contribute to our understanding of the immune failure mechanisms and confirm that (CXCL11/CXCR3) signal intensity is a key determinant of prognosis, making this axis a promising therapeutic target for modulating the tumor microenvironment.
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References
Mahdi D, Alzeyadi M, AL-Sallami AS. MicroRNA 29 gene Expression and Progesterone Receptor Values in Iraqi Women with Breast Cancer. Egyptian Journal of Medical Microbiology. 2025 Jan 1;34(1) https://doi.org/10.21608/ejmm.2024.319913.1337 .
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. The lancet oncology. 2018 Jan 1;19(1):40-50. https://doi.org/10.1016/s1470-2045(17)30904-x
Wang J, Ouyang X, Zhu W, Yi Q, Zhong J. The role of CXCL11 and its receptors in cancer: prospective but challenging clinical targets. Cancer Control. 2024 Mar 17;31:10732748241241162. https://doi.org/10.1177/10732748241241162
Tokunaga R, Zhang WU, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation–a target for novel cancer therapy. Cancer treatment reviews. 2018 Feb 1;63:40-7. https://doi.org/10.1016/j.ctrv.2017.11.007
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic acids research. 2023 Jan 6;51(D1):D638-46. https://doi.org/10.1093/nar/gkac1000
Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Computational and structural biotechnology journal. 2021 Jan 1;19:4101-9. https://doi.org/10.1016/j.csbj.2021.07.014
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA. Gene ontology: tool for the unification of biology. Nature genetics. 2000 May;25(1):25-9. https://doi.org/10.1038/75556
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American statistical association. 1958 Jun 1;53(282):457-81. https://doi.org/10.1080/01621459.1958.10501452
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A. NCBI GEO: archive for functional genomics data sets—update. Nucleic acids research. 2012 Nov 26;41(D1):D991-5. https://doi.org/10.1093/nar/gks1193
Kuo WH, Chang YY, Lai LC, Tsai MH, Hsiao CK, Chang KJ, Chuang EY. Molecular characteristics and metastasis predictor genes of triple-negative breast cancer: a clinical study of triple-negative breast carcinomas. https://doi.org/10.1371/journal.pone.0045831
Chen X, Meng C, Wang X, Wu Z, Sun X, Sun C, Zheng L, Li W, Jia W, Tang T. Exploring CCL11 in breast cancer: unraveling its anticancer potential and immune modulatory effects involving the Akt-S6 signaling. Journal of Cancer Research and Clinical Oncology. 2024 Feb 2;150(2):69. https://doi.org/10.1007/s00432-023-05600-6
Jamiyan T, Kuroda H, Yamaguchi R, Abe A, Hayashi M. CD68-and CD163-positive tumor-associated macrophages in triple negative cancer of the breast. Virchows Archiv. 2020 Dec;477(6):767-75. https://doi.org/10.1007/s00428-020-02855-z
Ni C, Yang L, Xu Q, Yuan H, Wang W, Xia W, Gong D, Zhang W, Yu K. CD68-and CD163-positive tumor infiltrating macrophages in non-metastatic breast cancer: a retrospective study and meta-analysis. Journal of Cancer. 2019 Jul 23;10(19):4463. https://doi.org/10.7150/jca.33914
Peng J, Liu X, Mao Y, Lv M, Ma T, Liu J, Zhou Q, Han Y, Li X, Wang H. Upregulation of collagen type X alpha 1 promotes the progress of triple‐negative breast cancer via Wnt/β‐catenin signaling. Molecular Carcinogenesis. 2024 Aug;63(8):1588-98. https://doi.org/10.1002/mc.23747
Pérez-Pena J, Tibor Fekete J, Páez R, Baliu-Piqué M, García-Saenz JÁ, García-Barberán V, Manzano A, Pérez-Segura P, Esparis-Ogando A, Pandiella A, Gyorffy B. A transcriptomic immunologic signature predicts favorable outcome in neoadjuvant chemotherapy treated triple negative breast tumors. Frontiers in immunology. 2019 Dec 18;10:2802. https://doi.org/10.3389/fimmu.2019.02802
Zhang X, Wu J, Hu C, Zheng X, Guo Z, Li L. CXCL11 negatively regulated by MED19 favours antitumour immune infiltration in breast cancer. Cytokine. 2023 Feb 1;162:156106. https://doi.org/10.1016/j.cyto.2022.156106
Hensbergen PJ, Wijnands PG, Schreurs MW, Scheper RJ, Willemze R, Tensen CP. The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis. Journal of immunotherapy. 2005 Jul 1;28(4):343-51. https://doi.org/10.1097/01.cji.0000165355.26795.27
Wu L, Sun S, Qu F, Sun M, Liu X, Sun Q, Cheng L, Zheng Y, Su G. CXCL9 influences the tumor immune microenvironment by stimulating JAK/STAT pathway in triple-negative breast cancer. Cancer Immunology, Immunotherapy. 2023 Jun;72(6):1479-92. https://doi.org/10.1007/s00262-022-03343-w
Cao X, Song Y, Wu H, Ren X, Sun Q, Liang Z. CXC motif chemokine ligand 9 correlates with favorable prognosis in triple-negative breast cancer by promoting immune cell infiltration. Molecular Cancer Therapeutics. 2023 Dec 1;22(12):1493-502. https://doi.org/10.1158/1535-7163.mct-23-0281
Montemagno C, Jacquel A, Pandiani C, Rastoin O, Dawaliby R, Schmitt T, Bourgoin M, Palenzuela H, Rossi AL, Ambrosetti D, Durivault J. Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001. Journal of experimental & clinical cancer research. 2024 Mar 19;43(1):86. https://doi.org/10.1186/s13046-024-02984-2
Cencini E, Fabbri A, Sicuranza A, Gozzetti A, Bocchia M. The role of tumor-associated macrophages in hematologic malignancies. Cancers. 2021 Jul 18;13(14):3597. https://doi.org/10.3390/cancers13143597
Fang C, Cheung MY, Chan RC, Poon IK, Lee C, To CC, Tsang JY, Li J, Tse GM. Prognostic significance of CD163+ and/or CD206+ tumor-associated macrophages is linked to their spatial distribution and tumor-infiltrating lymphocytes in breast cancer. Cancers. 2024 Jun 5;16(11):2147. https://doi.org/10.3390/cancers16112147
Cheng ZH, Shi YX, Yuan M, Xiong D, Zheng JH, Zhang ZY. Chemokines and their receptors in lung cancer progression and metastasis. Journal of Zhejiang University-SCIENCE B. 2016 May;17(5):342-51. https://doi.org/10.1631/jzus.b1500258
Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. International journal of molecular sciences. 2023 Feb 16;24(4):4002. https://doi.org/10.3390/ijms24044002
Gao Q, Zhang Y. CXCL11 signaling in the tumor microenvironment. Tumor Microenvironment: The Role of Chemokines–Part B. 2021 Jul 22:41-50. https://doi.org/10.1007/978-3-030-62658-7_4
Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nature reviews immunology. 2012 May;12(5):325-38 https://doi.org/10.1038/nri3198 .
Chen Y, Xu Z, Sun H, Ouyang X, Han Y, Yu H, Wu N, Xie Y, Su B. Regulation of CD8+ T memory and exhaustion by the mTOR signals. Cellular & Molecular Immunology. 2023 Sep;20(9):1023-39 https://doi.org/10.1038/s41423-023-01064-3 .
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. Journal of hematology & oncology. 2017 Feb 22;10(1):55 https://doi.org/10.1186/s13045-017-0417-z .
Tokunaga R, Zhang WU, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation–a target for novel cancer therapy. Cancer treatment reviews. 2018 Feb 1;63:40-7 https://doi.org/10.1016/j.ctrv.2017.11.007 .
Kishi M. Strategies of Cancer Immunotherapy: Model of Triple Negative Breast Cancer (Doctoral dissertation, Université Paris Saclay (COmUE)) https://theses.hal.science/tel-02527172/ .
Marcovecchio PM, Thomas G, Salek-Ardakani S. CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer. Journal for immunotherapy of cancer. 2021 Feb 26;9(2):e002045. https://doi.org/10.1136/jitc-2020-002045.
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