A sub‐population of cells expressing MYC and BCL2 without BCL6 refines the definition of double expressor lymphoma (DEL)
Year: 2023
Type: article
Abstract: Introduction: ‘Double Expressor Lymphomas’ (DEL) refer to high-risk diffuse large B-cell lymphoma (DLBCL) that are positive for MYC and BCL2 by immunohistochemistry (IHC). We recently demonstrated using single-cell resolved analysis that the extent of cells with a unique co-expression pattern of high MYC and BCL2 but lacking BCL6 (M+2+6-) drives prognosis in DLBCL. We now present a follow-up study evaluating clinical utility of the M+2+6- subpopulation with relation to DEL, and its relation to spatial and immune phenotypes in DLBCL. Methods: We measured M+2+6- percentage by multiplexed fluorescent IHC (mfIHC) in DEL cases from a DLBCL cohort classified by chromogenic IHC (British Columbia Cancer Agency (BCA), n = 89). A mathematical method to predict M+2+6- percentage extent was used to extend the analysis to DEL cases from two independent mRNA-based cohorts (GSE117556, n = 67; GOYA, n = 175). To evaluate for immune phenotypes and therapeutic vulnerabilities in cases with high M+2+6-, we performed Digital Spatial Profiling (DSP) analyses, applying the protein-based nCounter method (29 immune markers) to 110 DLBCL samples, and the Whole Transcriptome Atlas (WTA) analysis (18,000 genes) to CD3+ enriched regions of 47 DLBCL samples. Using a pan-immune protein-marker DSP panel, we identified that the T-cell immune regulators ICOS and 4-1BB were negatively correlated with M+2+6- percentage extent (r = −0.27, p = 0.0046; r = −0.22, p = 0.019, respectively), suggesting a potential role for ICOS or 4-1BB stimulatory therapeutics (e.g. feladilimab, utomilumab) in combination with chemotherapy for high M+2+6- cases. To molecularly characterize T-cells in relation to the presence of M+2+6- cells, we performed a DSP WTA analysis in CD3+ expressing cells in our DLBCL cohort. T-cells in cases with high M+2+6- fraction expressed distinct genes and pathways, and single-cell atlas mapping revealed an intriguing enrichment of naïve CD4 and CD8 populations. Conclusions: A simple mathematical formula for estimation of MYC+BCL2+BCL6- cells in DLBCL refines the DEL diagnosis, and could be of value in selecting high risk DLBCL for trials of novel agents. High M+2+6- DLBCL display unique T-cell infiltrates, and immunomodulation by ICOS and 4-1BB agonists could represent a therapeutic vulnerability for this high-risk subgroup. The research was funded by: ADJ was supported by the Singapore Ministry of Health’s National Medical Research Council Clinician Scientist Award (MOH-000715-00). Work in ADJ’s laboratory is funded by a core grant from the Cancer Science Institute of Singapore, National University of Singapore through the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. SBN was supported by the National Medical Research Council Senior Investigator Clinician Scientist Award (MOH-001104). Work by SBN and ADJ was also supported by the National Medical Research Council Open Fund Large Collaborative Grant, (SYMPhonY; NMRC OF-LCG18May-0028). CT was supported by the Italian Foundation for Cancer Research (AIRC) Investigator Grant IG ID.22145; 5 × 1000 Grant ID.22759. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract. C. Harris III Employment or leadership position: Carl Harris III is an employee of Roche A. Bottos Employment or leadership position: Alessia Bottos is an employee of Roche A. D. Jeyasekharan Consultant or advisory role: Roche, Gilead, Turbine Ltd, AstraZeneca, Antengene, Janssen, MSD and IQVIA Research funding: Janssen and AstraZeneca
Source: Hematological Oncology
DOI: 10.1002/hon.3164_208
Authors: M. M. Hoppe, S. Sridhar, M. Liu, P. Jaynes, Y. Peng, C. Harris, A. Bottos, P. Farinha, A. Mottok, D. W. Scott, Y. L. Chee, S. Ng, C. Tripodo, A. D. Jeyasekharan
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4380084815