CCL18: A potential immunosuppressive biomarker for prognosis in ABC diffuse large B-cell lymphoma

Marta Rodríguez-Moreno¹Francisco Rojas-Vega²Ignacio Mahíllo³Jesús Frutos¹Cristina Serrano Del Castillo⁴Alberto Lopez-Garcia⁵Teresa Morales-Ruiz²Teresa Roldan-Arjona²Joaquin Sanchez-Garcia⁶Ana Río-Machín^7,8Daniel Morillo⁵Raul Cordoba^5,7Pilar Llamas-Sillero^5,7Socorro María Rodríguez-Pinilla¹Juana Serrano Lopez^10,9*

• ¹Pathology Department, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
• ²Department of Genetics. University of Cordoba, Córdoba, Spain. Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain. Reina Sofía University Hospital, Córdoba, Spain, Cordoba, Spain
• ³Department of Epidemiology, Health Research Institute Foundation Jimenez Diaz (IIS-FJD), Madrid, Spain
• ⁴Immunology Department, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
• ⁵Hematology Department, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
• ⁶Hematology Department, Reina Sofía University Hospital/Maimonides Biomedical Research Institute of Córdoba (IMIBIC)/University of Córdoba, Spain, Cordoba, Spain
• ⁷Experimental Hematology Lab, Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain
• ⁸Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London ECM1M 5PZ, UK, London, United Kingdom
• ⁹Experimental Hematology Lab, Health Research Institute Foundation Jimenez Diaz (IIS-FJD), Madrid, Spain
• ¹⁰Facultad de Biomedicina, Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain

Background: Activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) has worse outcomes than germinal center B-cell (GCB) subtype, but underlying molecular mechanisms remain poorly understood. Methods: We performed transcriptomic analysis on 43 DLBCL samples (23 GCB, 20 ABC) using NanoString PanCancer Immune Profiling Panel with 30 cell-of-origin genes. Tumor microenvironment characterization used CIBERSORTx and GSEA deconvolution. Based on our previous findings of MAPK10 downregulation in ABC lymphomas, MAPK10 promoter methylation was studied via pyrosequencing. Prognostic biomarkers were identified using Cox regression and LASSO regularization. Therapeutic candidates were identified through connectivity mapping. Results: ABC lymphomas showed distinct profiles with overexpression of VTCN1, CDK4, and CXCR5, and downregulation of MMP9 and MAPK10. GSEA revealed enrichment of inflammatory pathways with immunosuppressive signals in ABC cases. Confirming our prior observations, MAPK10 downregulation in ABC tumors was associated with promoter hypermethylation and inferior overall survival (p<0.01). Immune deconvolution revealed greater microenvironmental diversity in ABC cases with significant eosinophil enrichment. High CD8+ T cell abundance was associated with improved survival, particularly in ABC patients (p<0.01). Multivariate analysis identified CCL18 as an independent adverse prognostic factor (HR: 1.87, 95% CI: 1.25-2.79, p<0.01). Connectivity mapping identified proteasome inhibitors and CDK4/6 inhibitors as promising therapeutic candidates. Conclusions: We validate MAPK10 promoter hypermethylation and CCL18 overexpression as prognostic biomarkers in ABC DLBCL. These findings, derived from integrative transcriptomic and immunogenomic profiling provide clinically relevant insights into disease biology and support biomarker-guided strategies for precision treatment in aggressive B-cell lymphomas.