Abstract Background - The tumor microenvironment (TME) plays a vital role in the growth and survival of mantle cell lymphoma (MCL) cells. However, characterization of the TME transcriptomic profile in MCL, its prognostic impact and response to Bruton's tyrosine kinase inhibitors (BTKi) is unknown. Unlike other lymphomas, the TME in MCL patients has not been fully characterized at the transcriptomic and genomic levels. To further understand the relevance of tumor-immune landscape in tissue microenvironments in the context of BTKi, we performed multi-omic profiling of the TME in tissues from MCL patients. Methods - Tissue biopsies were collected from MCL patients treated with BTKi. The study was conducted under an Institutional Review Board-approved protocol at The University of Texas MD Anderson Cancer Center. A total of 42 patients treated with BTKi were included. Among evaluable patients, DNA and RNA extraction was performed from fresh biopsies from lymph nodes and non-nodal tissues (including bone marrow). Whole exome (WES) and bulk RNA sequencing (RNA-seq) were performed to assess the somatic mutation profile, copy number abnormalities and gene expression profile to identify TME gene clusters. RNA sequencing data from an independent cohort of MCL patients from Scott et al (n = 122) was analyzed. Joint WES and RNA-seq, mutation calling, expression analysis, and cell type deconvolution from the transcriptome were performed using the BostonGene automated pipeline. Overall survival was calculated after starting BTKi therapy. Results - We obtained 42 MCL tissue samples (28 lymph nodes, 13 various tissues and one bone marrow) from patients treated with BTKi. Samples were obtained at/after starting treatment with BTKi at clinical progression. Unsupervised clustering based on the activities of the proposed transcriptomic signatures identified four distinct MCL subtypes based on tumor-immune cell gene signatures. We identified the four distinct MCL microenvironment signatures - normal lymph node like (N; n = 27), immune cell-enriched or "Hot" (IE; n = 46), mesenchymal (M; n = 44) and immune depleted/deserted or 'cold' (D; n = 51). The tumor proliferation rate signature and PI3K pathways were significantly overexpressed in immune-depleted (D) TME group. Evaluable patients were further classified based on response to BTKi as sensitive (n = 17), primary resistant (n = 11) or acquired resistant (n = 11). The TME was further dichotomized into immune cell rich and immune desert categories based on commonly involved immune cells and pathways. BTKi resistant MCL primarily exhibited immune depleted TME subtype. To explore the somatic mutation profile in relation to TME clusters, we performed a multiomic analysis combining WES data with RNA sequencing data and depicted according to the four TME clusters. Somatic mutations in 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 immune-depleted TME cluster (D). Conclusions - Overall, we defined BTKi sensitivity and resistance by immune-hot and immune-cold TME portraits, respectively. The immune-depleted TME subtype (D) was characterized by dominant proliferation gene signature, overexpressed PI3K pathway, BTKi resistance and poor outcomes in MCL patients. Disclosures Jain: Lilly: Consultancy; kite: Consultancy. Nomie: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Segodin: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Egorov: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Vega: CRISPR Therapeutics and Geron: Research Funding; i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding. Svekolkin: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Frenkel: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Attaulakhanov: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Sanofi: Research Funding; Amgen: Research Funding; EMD: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Denovo: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Epizyme, Inc.: Consultancy; Morphosys: Research Funding; Genmab: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy; Kite: Research Funding; Guardant: Research Funding; SeaGen: Consultancy; Cellectis: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; Spectrum: Consultancy; Acerta: Research Funding; 4D: Research Funding; Pharmacyclics: Research Funding. Wang: BGICS: Honoraria; Newbridge Pharmaceuticals: Honoraria; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mumbai Hematology Group: Honoraria; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Loxo Oncology: Consultancy, Research Funding; Moffit Cancer Center: Honoraria; Lilly: Research Funding; Bayer Healthcare: Consultancy; OMI: Honoraria; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Clinical Care Options: Honoraria; Dava Oncology: Honoraria; CStone: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding.