B-cell receptor signaling and microenvironment crosstalk in mantle cell lymphoma

Mantle Cell Lymphoma (MCL) is a B-cell neoplasm with a high incidence of relapse, even after the introduction of novel targeted therapies. MCL cells develop in specialized tissue microenvironments such as bone marrow and secondary lymphoid organs, where the pathological cells interact with several microenvironmental components through a complex network of soluble factors and adhesion molecules. This dynamic and complex system, including the activation of B-cell receptor signaling (BCR), promotes survival, immune evasion, and therapeutic resistance. Given the central role of the BCR signaling pathway in proliferation and survival of neoplastic B lymphocytes, in the last decades several biological agents against the key BCR proteins, i.e. Bruton Tyrosine Kinase inhibitors (BTKi), have been developed, and they represent the most effective treatment for MCL management. Importantly, BTKi response is influenced by the type of BCR signaling preferentially adopted by MCL cells and the composition of the tumor microenvironment. The present review summarizes and elucidates the mechanisms by which MCL cells and their microenvironments interact and how MCL cells integrate these interactions with the BCR signaling, highlighting the involvement of these external cues on MCL pathogenesis, progression, and treatment.