Session: 621. Lymphoma—Genetic/Epigenetic Biology: Poster III
Hematology Disease Topics & Pathways:
Diseases, Biological Processes, T-Cell Lymphoma, Technology and Procedures, Lymphoid Malignancies, genetic profiling, flow cytometry, NGS, microenvironment, RNA sequencing, pathogenesis
Within malignant cells, we identified a fraction of cycling cells present across most ATL samples. This fraction showed an enhanced T-cell activation markers, such as CD25 and HLA-DR, and their frequency was increased in aggressive subtypes. On the other hand, in HTLV-1-infected carriers, HTLV-1-infected CD4+ T cells contained a small population of malignant-like cells showing clonal expansion. The degree of clonal expansion was significantly correlated with HTLV-1 viral load in PBMCs. These results clarify the heterogeneity within HTLV-1-infected cells and ATL malignant cells, pointing to its relevance during ATL initiation and progression.
We also observed dynamic changes of the immune microenvironment in ATL. Although the relative frequencies of other cell types remained almost the same or reduced, only myeloid cells were increased in ATL patients compared with in HTLV-1-infected carriers. Re-clustering of myeloid cells identified a novel cluster of monocytes expressing FCGR1A, encoding CD64, a biomarker of IFN-stimulated gene levels. Transcriptome analysis revealed increased IFN signaling and decreased TNFa in myeloid cells from ATL patients compared with HTLV-1-infected carriers. Similar expression signatures changes were also observed in various immune cell types, such as B, CD8+ T, and NK cells, in ATL patients. In addition, substantial changes of surface marker proteins were also found in ATL patients. Particularly, T-cell activation markers, such as HLA-DR, and inhibitory immune checkpoint molecules, such as PD-1 and TIM-3, were up-regulated in CD8+ T cells from ATL patients. A co-culture experiment of ATL cell lines with PBMCs from healthy volunteers demonstrated that ATL cells induced immune-phenotypic changes of myeloid and CD8+ T cells, similar to those observed in ATL patient by our single-cell analysis, confirming the role of ATL cells in the modulation of the immune system. Taken together, the composition and function of immune microenvironment is dramatically altered in ATL patients, which may contribute to immunosuppression and disease progression in ATL.
In summary, our multi-omics single-cell analysis comprehensively dissects the cellular and molecular architecture in HTLV-1-infected carriers and ATL patients. In particular, our approach clearly defines HTLV-1-infected cells by the expression of HTLV-1-related genes, leading to the detailed characterization of HTLV-1-infected cells and elucidation of their difference from ATL malignant cells. These findings will help to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.
Disclosures: Kogure: Takeda Pharmaceutical Company Limited.: Honoraria. Shimoda: Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Shire plc: Honoraria; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding. Kataoka: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company.
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