PI3Kδ INHIBITION RESHAPES FOLLICULAR LYMPHOMA - IMMUNE MICROENVIRONMENT CROSSTALK AND UNLEASHES THE ACTIVITY OF VENETOCLAX
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Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of PI3K inhibition, biomarkers of response andpotential combinatorial therapies in FL remain to be established. Using ex vivo co-cultures of FL patient biopsies and follicular dendritic cells (FDC) to mimic germinal center (n=42), we have uncovered that PI3K inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation and transendothelial migration in a subset of FL samples, defining a 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases, was its interference with CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B-T cell synapses, leading to an inefficient crosstalk between FL cells and the supportive T follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling we have uncovered that FL-FDC and FL-macrophages co-cultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity towards angiogenesis and lymphoma dissemination. In all FL cases idelalisib exerts a general reshaping of FL immune microenvironment and restores dependence on BCL-2 predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3K inhibitors and venetoclax in clinical trials.
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2473-9537
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Medical Research Council (MR/M008584/1)
Medical Research Council (MC_PC_17230)