Immune-depleted tumor microenvironment is associated with poor outcomes and BTK inhibitor resistance in mantle cell lymphoma
Preetesh Jain, Krystle Nomie, Nikita Kotlov, VitaIy Segodin, Holly A. Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal‐Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R. Flowers, Michael Wang
Abstract
Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [ 1 ]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [ 2 ]. A few reports have also demonstrated that a decrease in T cell numbers [ 3 , 4 ] or a downregulation of effector/cytotoxic T cells [ 5 , 6 ], high Tregs [ 7 ] or a decreased expression of T cell activation/co-stimulation pathways [ 5 ] are associated with resistant MCL. An understanding of the tumor microenvironment (TME) and its cellular and analyte composition plays a critical role in promoting MCL cell growth, proliferation [ 8 ] and treatment resistance [ 6 ]. Unlike other lymphomas [ 9 ], the TME in MCL patients has not been fully characterized at the transcriptomic and genomic levels. To further understand the relevance of the tumor-immune landscape in tissue microenvironments, we performed multiomic profiling to characterize the TME in tissues from MCL patients and examined the relationship between TME subtypes and their impact on clinical outcome and the response to BTKi.