PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax

Abstract

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B–T-cell synapses, leading to an inefficient cross talk 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 uncovered that FL–FDC and FL–macrophage cocultures 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 toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

“…FL-FDC cross-talk induces a pro-angiogenic expression pattern in FL cells, including secretion of VEGF-A and VEGF-C ( 255 ). This cross-talk is crucially dependent on the phosphoinositide-3-kinase δ (PI3Kδ), providing therapeutic intervention options with PI3K specific inhibitors like idelalisib, which is approved for the treatment of FL, CLL, and SLL ( 256 ). The second branch of the supportive infrastructure in follicles are the CD4 + CXCR5 + PD1 + T follicular helper (Tfh) cells, which provide vital survival signals for FL cells by secreting IL2, IL4, IFNγ, and by CD40L presentation ( 9 , 257 ).…”

The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma

“…We have established primary FL-FDC co-cultures using FL samples mostly from LN biopsies (composed mainly by tumor B cells and several T subpopulations including TFH, regulatory, and cytotoxic T cells) and supportive FDC (HK cell line) generated from tonsils of normal donors previously used to mimic de GC [22] and promote B-cell survival [23]. Using this primary co-culture model, we previously reported that FL-FDC crosstalk shapes key lymphoma features including adhesion, dissemination, angiogenesis, and ECM remodeling, among others [21,39].…”

Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

“…The net balance of these effects might result in inefficient crosstalk between FL cells and the supportive T FH cells. Moreover, the chemokine CCL22, fundamental in the FL milieu, decreases after idelalisib treatment, and this phenomenon impacts on the composition of FL microenvironment by a decrease in the recruitment of T REG and T FH , but not T FR into FL-FDC niche, which may allow the host to mount superior immune responses against the tumor [ 60 ].…”