Tumor heterogeneity and immune-evasive T follicular cell lymphoma phenotypes at single-cell resolution

• Published in: Leukemia 2024-02, Vol.38 (2), p.340-350
• Main Authors: Suma, Sakurako, Suehara, Yasuhito, Fujisawa, Manabu, Abe, Yoshiaki, Hattori, Keiichiro, Makishima, Kenichi, Sakamoto, Tatsuhiro, Sawa, Aya, Bando, Hiroko, Kaji, Daisuke, Sugio, Takeshi, Kato, Koji, Akashi, Koichi, Matsue, Kosei, Carreras, Joaquim, Nakamura, Naoya, Suzuki, Ayako, Suzuki, Yutaka, Ito, Ken, Shiiba, Hiroyuki, Chiba, Shigeru, Sakata-Yanagimoto, Mamiko
• Format: Article
• Language: English
• Subjects: 38/39; 631/67/1059/2326; 631/67/1990/291/1621/1916; 631/67/327; 631/67/69; 82/51; Biomarkers, Tumor - analysis; Cancer Research; CD8 antigen; CD8-Positive T-Lymphocytes; Cell growth; Cell proliferation; Chemokines; Cloning; Copy number; Critical Care Medicine; Cytokines; DNA Copy Number Variations; Flow cytometry; Hematology; Heterogeneity; Humans; Immune system; Intensive; Internal Medicine; Killer Cells, Natural; Leukemia; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Lymphoma; Lymphoma, Follicular - pathology; Medical prognosis; Medicine; Medicine & Public Health; Metastases; Microenvironments; Mutation; Natural killer cells; Oncology; Peripheral blood; Phenotype; Phenotypes; Spatial analysis; T-Lymphocytes, Helper-Inducer; Trajectory analysis; Transcriptomics; Treatment resistance; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-023-02093-7

T follicular helper (T FH ) cell lymphomas (TFHLs) are characterized by T FH -like properties and accompanied by substantial immune-cell infiltration into tumor tissues. Nevertheless, the comprehensive understanding of tumor-cell heterogeneity and immune profiles of TFHL remains elusive. To address this, we conducted single-cell transcriptomic analysis on 9 lymph node (LN) and 16 peripheral blood (PB) samples from TFHL patients. Tumor cells were divided into 5 distinct subclusters, with significant heterogeneity observed in the expression levels of T FH markers. Copy number variation (CNV) and trajectory analyses indicated that the accumulation of CNVs, together with gene mutations, may drive the clonal evolution of tumor cells towards T FH -like and cell proliferation phenotypes. Additionally, we identified a novel tumor-cell-specific marker, PLS3. Notably, we found a significant increase in exhausted CD8 + T cells with oligoclonal expansion in TFHL LNs and PB, along with distinctive immune evasion characteristics exhibited by infiltrating regulatory T, myeloid, B, and natural killer cells. Finally, in-silico and spatial cell-cell interaction analyses revealed complex networking between tumor and immune cells, driving the formation of an immunosuppressive microenvironment. These findings highlight the remarkable tumor-cell heterogeneity and immunoevasion in TFHL beyond previous expectations, suggesting potential roles in treatment resistance.