Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL

In this study high-plex spatial profiling of patient lymph node sections was performed using the Orion instrument (RareCyte, Inc.), enabling 15-color multiplex immunofluorescence staining. This spatial analysis reveals that T cells in CLL lymph nodes exhibit the most distinct profiles, characterized by a significant accumulation of regulatory T cells and CD8+ T cells in various exhaustion states, specifically precursor (TPEX) and terminally exhausted (TEX) subsets. Integration of T-cell receptor sequencing data with the predicTCR classifier suggests a localized enrichment of CLL-reactive T cells within these lymphoid tissues. Furthermore, interactome studies identify promising immunotherapy targets, most notably galectin-9, a ligand for TIM3. In vivo inhibition of galectin-9 in mouse models results in reduced disease progression and a decrease in TIM3+ T cells. Given that galectin-9 expression correlates with poorer survival outcomes in CLL and other malignancies, these findings underscore its role in immune evasion and its viability as a therapeutic target.

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