Faculty, Staff and Student Publications
Publication Date
10-12-2023
Journal
Blood Cancer Journal
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.
This cohort study was conducted under an IRB approved protocol for MCL patients at our Center. Tissue biopsies (30 lymph nodes and 11 other tissues) were collected from 41 patients with MCL (patient characteristics in supplemental Table 1). Samples were obtained at progression in patients who were resistant or before starting treatment with BTKi in patients who were sensitive to BTKi. Primary BTKi resistant MCL were patients who never responded while acquired resistant MCL were those who had either a partial or complete response to BTKi and subsequently progressed. Among evaluable patients, DNA and RNA extraction was performed from fresh biopsies from lymph nodes and non-nodal tissues. Whole exome (WES) and bulk RNA sequencing were performed to assess the somatic mutation profile, copy number abnormalities and gene expression profile to identify TME gene clusters. RNA sequencing data were combined with data from an independent cohort of MCL patients [Scott et al. (n = 122)] [10]. Fig. 1A displays the study design. Joint WES and RNA-seq mutation calling, expression analysis, and cell deconvolution from the transcriptome were performed using the BostonGene automated pipeline [9]. All WES and bulk RNA sequencing was performed with Illumina HiSeq4000 using a 76 bp paired end configuration (described in the supplemental file). Overall survival was calculated from the initiation of BTKi therapy until death or the date of last follow up (censored).
Keywords
Humans, Adult, Lymphoma, Mantle-Cell, Tumor Microenvironment, Protein-Tyrosine Kinases, Protein Kinase Inhibitors
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Medical Sciences Commons, Oncology Commons
Comments
Associated Data
PMID: 37821434