IMMUNE‐DEPLETED TUMOR MICROENVIRONMENT IS ASSOCIATED WITH POOR OUTCOMES AND BTK INHIBITOR RESISTANCE IN MANTLE CELL LYMPHOMA

Abstract

Introduction: An understanding of the tumor microenvironment (TME) and its cellular and analyte composition plays a critical role in promoting mantle cell lymphoma (MCL) cell growth, proliferation. 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. Methods: This cohort study was conducted under an IRB approved protocol for MCL patients at our Center. Tissue biopsies (28 lymph nodes and 13 other tissues) were collected from 41 patients with MCL. We conducted whole exome sequencing (WES; n = 41) and RNA-seq (n = 41) from MCL tissue biopsies from patients treated with BTKi (ibrutinib, acalabrutinib or zanubrutinib) in combination with the analysis of a published MCL cohort (n = 122). Joint WES and RNA-seq mutation calling and TME molecular signatures were categorized based on response to BTKi. All WES and bulk RNA sequencing was performed with Illumina HiSeq4000 using a 76 bp paired end configuration. Results: Unsupervised clustering identified four MCL TME subtypes reflecting distinct tumor-immune cell gene signatures. Four distinct groups—normal lymph node (n = 27), immune cell-enriched (n = 46), mesenchymal (n = 44) and immune cell-depleted “D” (n = 51). “D” subtype was predominant in patients with primary BTKi resistance. A high tumor proliferation gene signature was observed exclusively in the “D” group. We further observed that Ki-67% from tissue biopsies had a linear correlation with proliferation rate signature genes and significantly overexpressed in the D group (p = 0.002). Somatic mutations such as TP53, NSD2, NOTCH1, KMT2D, SMARCA4, which were previously reported in ibrutinib-resistant MCL and/or in refractory high-risk MCL patients, were predominant in the Dsubtype. Finally, the evaluable patients (n = 39) were divided according to response to BTKi- sensitive, primary resistant and acquired resistant and MFP clusters. Patients with primary and acquired resistance had significant proportion of patients with D subtype (p = 0.004), compared to N and IE subtypes. Primary and BTKi resistant patients had a trend of inferior survival compared to sensitive patients (p = 0.07). Furthermore, we demonstrated that the D TME group had worse overall survival compared to other TME categories (p = 0.001). Keyword: microenvironment The research was funded by: Boston Gene Corp