Multiomics Analysis of Paired Diagnosis and Relapse DLBCL Biopsies Shows a Reduction in T Cell Infiltration and Function at Relapse

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.3006-3006
• Main Authors: Swain, Fiona, Burgess, Melinda, Kempe, Sarah, Sabdia, Muhammed B., Henden, Andrea S, Wight, Joel, Hawkes, Eliza A., Mutsando, Howard, Talaulikar, Dipti, Merida de Long, Lilia, Birch, Simone, Wyche, Penelope, Hawula, Zachary, Chowdhury, Rakin, Gandhi, Maher K., Keane, Colm
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-199352

Introduction Despite introduction of innovative immune based therapies, many patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) continue to have poor outcomes. Defining immune changes that occur within tumors at relapse is crucial to understanding treatment failure. To explore the evolution of the tumor microenvironment (TME) across treatment timepoints, we performed comprehensive multiomics analysis encompassing immune gene expression, T-cell receptor (TCR) sequencing and spatial transcriptome analysis in a large Australian cohort of R/R DLBCL patients with paired diagnosis and relapse biopsies. Methods Archived biopsies from 141 clinically annotated R/R DLBCL patients were collected from 6 Australian centres. Gene expression profiling using the Nanostring PanCancer Immune panel of 770 immune-related genes was performed on 125 diagnostic and 124 R/R biopsies (first R/R episode: 102, subsequent R/R episode: 22). Lymphoma Subtype (LST) signature was used to evaluate cell of origin (COO). TCR sequencing was performed on 22 pairs using the Archer Immunoverse RNA assay. Nanostring GeoMx spatial whole transcriptome assay was performed on 17 diagnostic and 6 R/R biopsies, segmented into CD20, CD8, CD4 and CD68 regions. Results 63 R/R patients were assigned germinal centre B cell (GCB) COO, 41 activated B cell (ABC), and 19 were unclassified. Only 2 late relapsing (LR) patients (relapse >12 months post end of treatment [EOT]) had COO discordance. COO was not prognostic at relapse. Differential immune gene expression (corrected for false discovery) on 87 pairs of diagnosis and R/R biopsies demonstrated profound changes in the T cell compartment. T cell associated genes (CD3E, CD5, CD7, CD8A, CXCL9: adj p