Lymphoma tissue explants to anticipate response to targeted therapies

The concept of precision medicine emerged to match targeted therapies with the genomic fingerprint of each cancer patient. However, the cellular composition and architecture of tumor tissues are additional parameters that influence response to therapies. B-cell lymphomas are a heterogenous group of tumors emerging from B cells in different stages of differentiation in specialized areas of the lymph nodes. Therefore, in order to reliably anticipate responses to treatment, lymphoma models must preserve the spatial organization and the functional interdependency between the malignant and non-malignant cells. Modeling lymphoma ex vivo has been hampered by the lack of suitable 3D models and the complexity of translating organoid technology -which is mainly based on the presence of tumor sustaining cancer stem cells- from other cancer types into lymphoma. To address these challenges, we have designed an ex vivoculture system for lymphoma tissues using murine models. FACS analyses, single-cell RNA sequencing, and high-plex spatial proteomic analyses confirm that our system is able to support tumor growth and tissue architecture. As they retained histological, cellular, and molecular characteristics distinctive of the original tissue, we called them lymphomoids. To anticipate sensitivity to anti-cancer therapies, we tested response to targeted therapies on lymphomoids obtained from human primary lymphomas. Histopathological and spatial transcriptomic analyses showed patient-specific sensitivity to particular compounds and revealed features on the tumor tissue composition associated with resistance or response to therapies. Importantly, in three cases the response to therapy observed in the lymphomoids anticipated the patient’s clinical outcome. All in all, lymphomoids represent an innovative tool to assess therapy response in lymphoma patients and uncover novel aspects of lymphoma biology. The research was funded by: Fondation Aclon, Accentus Foundation, and the Fondazione San Salvatore. Keywords: Microenvironment, Tumor Biology and Heterogeneity No conflicts of interests pertinent to the abstract.