P-078: Prognostic value of immune cells in the multiple myeloma bone marrow microenvironment: a meta-analysis within silico and in vitro validation

Abstract

<h3>Background</h3> During multiple myeloma (MM) immunoediting, the immune cells can be effective in eliminating the initiating tumor MM cells (MMPCs) in the elimination phase or at least, in the equilibrium phase, which can prompt functional dormancy at early stages. However, malignant MMPCs can take advantage of immune dysfunction and permissive immune microenvironment to escape immune elimination, proliferate and generate active MM. <h3>Methods</h3> We performed a systematic literature search of public databases through July 2021, investigating predefined biomarkers and immune-microenvironment MM component and their association with survival following PRISMA guidelines. The following search terms (MeSH) were used on each database: (multiple myeloma) AND (mast cell* OR macrophage* OR dendritic cell* OR NK cell* OR regulatory T cell* OR CD3 T-lymphocyte* OR CD4 T-lymphocyte* OR CD8 T-lymphocyte* OR B cell* OR CTLA-4 antigen* OR Antigen* CD274 OR PD-L1 OR PD1 OR BCMA OR SLAMF7) AND (observational OR case-control OR cohort OR overall-survival OR OS). To corroborate our data and investigate at a gene-expression level the prognostic value of deregulated genes (FDR<0.1 & P<0.05) we used a Cox-regression model in the CoMMpass dataset (n=326, IA15 release). We defined gene sets for 7 categories of T cell evasion, including the presence of immune suppressor cells, immune checkpoints, metabolic checkpoints, stromal cells, imbalanced antigen presentation, tumor cell death, and occurrence of oncogenic pathways. Gene expression analysis from pre-treatment bone marrow samples, purified for plasma cells followed 2 stages: first, we obtained ridge regression Cox models for overall survival (OS) for sets of genes that represent T cell evasion in a discovery set which were applied to the validation set; next, we tested each individual gene per gene set versus OS in Cox regression analysis. <h3>Results</h3> Studies that adjusted for important clinical covariates (such as international staging system ISS and revised-ISS) showed that higher levels of CD8+ cytotoxic T cells were associated with improved OS (HR = 0.69; 95% CI, 0.55–0.95) and PFS (HR = 0.70; 95% CI, 0.42–0.89), while increased CD 56/57+ NK cells (HR = 0.54; 95% CI, 0.27–0.91) were associated with improved OS; MM with increased FoxP3+ T regulatory cells (HR = 2.23; 95% CI, 1.45–3.36) had worse OS. Analyzing individual genes resulted in 33 genes that showed a significant association with OS in the discovery cohort and the remaining 4 genes in the validation cohort. These genes predominantly belonged to the family of immune checkpoint ligands being represented by ITGB1 (HR 0.69; CI 0.61-0.83), CD40 (HR 0.74; CI 0.62-0.89), TIM3 (HR 0.81; CI 0.72-0.91), and FABP5 (HR 0.78; CI 0.69-0.92). Subsequently, we functionally validated the downstream pathways related to cytoskeleton rearrangement, proliferation, epithelial-mesenchymal transition, and dissemination in vitro. <h3>Conclusions</h3> Conclusively, we propose this immune basket as a promising theragnostic tool in MM.