Lymphomoids: A Tissue-based Ex Vivo Culture System for Lymphoma Therapy Screening

The efficacy of anti-cancer therapies depends on the genomic composition of the tumor, its microenvironment, spatial organization, and intratumor heterogeneity. B-cell lymphomas are a heterogeneous group of tumors emerging from B-cells at different stages of differentiation and exhibiting tumor-specific interactions with the tumor microenvironment.

Thus, to measure response to therapy in lymphoma, it is critical to preserve the tumor composition and functional interactions among immune cells. The EPFL team recently developed a platform to culture and maintain small fragments of human lymphoma tissue (ex vivo) in the xeno-free, synthetic VitroGel® hydrogel system for several days, and they used them to test response therapies. Patient-derived tissue explants in the VitroGel® system preserve the original tissue’s histological, cellular, and molecular characteristics, allowing for the screening of sensitivity to targeted therapies in lymphoma.

The EPFL team collected 27 patient samples of different lymphoma subtypes and established ex vivo tissue fragments. FACS analyses, single-cell RNA sequencing, multiplex IHF, and spatial transcriptomics confirmed that tissue explants in the system retained histological, cellular, and molecular characteristics of the original tissue, hence we called these tissue explants lymphomoids. The EPFL team then uses them to test sensitivity to several clinically approved small molecule inhibitors in parallel and examine tissue remodeling upon treatment. Importantly, when this information was available, it showed that sensitivity to therapy observed in lymphomoids was largely consistent with the patient’s response in the clinic. Lymphomoids are an innovative tool to assess treatment efficacy in clinically relevant contexts and could be used to uncover novel aspects of lymphoma biology.

KEY TAKEAWAYS:

• Lymphomoids are lymphoma avatars that preserve the tissue composition.
• Lymphomoids support the tumor microenvironment (TME).
• Lymphomoids can predict sensitivity to targeted therapies in lymphoma.

Dr. Albert Santamaria-Martínez is a cancer researcher at EPFL (Lausanne, Switzerland). He earned his PhD from the University of Barcelona in 2009 before moving to Switzerland for postdoctoral training in the laboratory of Prof. Joerg Huelsken at EPFL. His work during this period earned him the Pfizer Prize in Oncology (2013) and was included in the second edition of The Biology of Cancer by R. Weinberg.

In 2014, Dr. Santamaria-Martínez was awarded an SNF Ambizione grant, which allowed him to lead an independent research group at the University of Fribourg (Switzerland). There, he focused on the tumor microenvironment, cancer stem cells, and metastasis.

In 2020, he joined the laboratory of Prof. Elisa Oricchio at EPFL to develop lymphoma avatars from human tissues, a project recently published in Nature Communications (Volume 15, Article 10650, 2024). His research centers on understanding tumor cell tolerances and needs—conceptually defined by the boundaries within which tumors can survive, grow, and metastasize.

Dr. Santamaria-Martínez is currently leading a collaborative effort between EPFL and various Swiss hospitals to establish a tissue explant and organoid platform for personalized oncology.