Unraveling MCL biology to understand resistance and identify vulnerabilities

Mantle cell lymphoma (MCL) is a rare (5%-7%), aggressive B-cell non-Hodgkin lymphoma with well-defined hallmarks (eg, cyclin D1, SOX11), and its expansion is highly dependent on the tumor microenvironment (TME). Parallel drastic progress in the understanding of lymphomagenesis and improved treatments led to a paradigm shift in this B-cell malignancy with now prolonged disease-free survival after intensive chemotherapy and anti-CD20-based maintenance. However, this toxic strategy is not applicable in frail or older patients, and a small but significant part of the cases present a refractory disease representing unmet medical needs. Importantly, the field has recently seen the rapid emergence of targeted and immune-based strategies with effective combinations relying on biological rationales to overcome malignant plasticity and intratumor heterogeneity. In this review, we expose how unraveling the biology of MCL allows to better understand the therapeutic resistances and to identify neo-vulnerabilities in tumors, which are essential to offer efficient novel strategies for high-risk patients. We first highlight the tumor intrinsic resistance mechanisms and associated Achilles heels within various pathways, such as NF-κB, mitochondrial apoptosis, DNA repair, and epigenetic regulators. We then place the tumor in its complex ecosystem to decipher the dialog with the multiple TME components and show how the resulting protumoral signals could be disrupted with innovative therapeutic strategies. Finally, we discuss how these progresses could be integrated into a personalized approach in MCL.