Lymphoid Organoids to Study Immune Synapse in Lymphoma Therapies

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in Europe and worldwide with more than 463/100 000/year.

Activated B cell (ABC)-DLBCL represents the more aggressive and chemo-resistant subtype to the frontline therapy Rituximab (R)-CHOP (doxorubicin, vincristine, prednisone, mechlorethamine) with 40% of patients experiencing no response or relapse. Therefore, new treatments are needed to improve the clinical outcome of ABC-DLBCLs.

A newly defined characteristic feature of the ABC-DLBCL subtype is the concurrent constitutive activation of B cell receptor (BCR) and Toll-like receptor (TLR) pathways that result in the upregulation of the NF-ĸB through cooperative signaling.

In ABC-DLBCLs the NF-ĸB signal is mediated from the downstream regulator Mucosa-associated lymphoid tissue lymphoma translocation protein 1(MALT1) paracaspase that is upregulated in 70% of these tumors..

For this reason, MALT1 paracaspase has become an attractive therapeutic target and MALT1 inhibitors have been developed..

However, previous studies indicate that approximately 63% of patients respond to BCR pathway inhibitors, and therefore understanding factors such as the intricate survival signals imparted by the lymph node tumor microenvironment (LymphTME) in ABC-DLBCL is critical for clinical translation of MALT1 inhibitors.

Two key elements of the LymphTME are the infiltration of T helper cell (Th) and the activation of ECM mediated pathways.

The Aim of LOISE project is to establish an ex vivo organoids that will mimic the T immunological synapse and ECM features with the purpose to elucidate their role on ABC-DLBCL survival and signaling response to BCR pathway inhibitors. These organoids will be used to designed a combinatorial targeted therapy for ABC-DLBCL.