Stefano CASOLA

Wednesday, 11 May 2022 | 12.00 noon – ICGEB Trieste, ITALY

IFOM the FIRC Institute of Molecular Oncology, Milan ITALY

B cell receptor influence on lymphoma immune surveillance in preclinical models of aggressive B cell lymphomas

(Host: G. Del Sal)

The B cell antigen receptor (BCR) represents a key determinant in emanating life and death signals to B-lymphocytes. BCR essentiality is conserved in most forms of leukemias and lymphomas arising from mature B cells. This knowledge has led to the development of small-molecule drugs targeting seleceted effectors of the BCR signaling pathway, with the goal to contrast tumor growth in B cell leukemia/lymphoma patients. The potent anti-leukemia/lymphoma activity of so-called BCR inhibitors (BCRi) seen in the clinical settings, is counterbalanced by emerging resistances to such treatments. These observations establish the property of malignant B cells in different lymphoma/leukemia subtypes to bypass the requirement for selected BCR signaling pathways for tumor growth. Understanding how lymphoma/leukemic B cells overcome BCR dependence, adapting to its functional inactivation, is key for a correct use of BCRi in the treatment of several forms of B cell malignancies. Moreover, unveiling the modes through which malignant B cells chronically adapt to the interference with the function of key BCR effectors is important for the design of novel therapeutic strategies targeting possible signaling/metabolic addictions (epi)genetically acquired by BCR-independent tumors. In order to tackle these questions, we have developed a pre-clinical mouse model in which we can closely monitor acute and chronic adaptive responses of aggressive MYC-driven B cell lymphomas to inducible extinction of BCR signals, while the malignant B cells are expanding in an immunocompetent setting in vivo.

The seminar will focus on unpublished results highlighting the importance of the BCR in regulating lymphoma immune surveillance, describing tumor cell-intrinsic determinants and immune cell subsets influencing the fine balance between tumor growth and immune rejection in vivo. The results will be discussed in the frame of a broader picture supporting a scenario whereby potentiating specific arms of the immune system may help to overcome chronic adaptation to pharmacological interference and/or sporadic acquired extinction of the BCR in aggressive forms of B cell lymphomas.