Tumor heterogeneity and immune-evasive T follicular cell lymphoma phenotypes at single-cell resolution
Sakurako Suma, Yasuhito Suehara, Manabu Fujisawa, Yoshiaki Abe, Keiichiro Hattori, Kenichi Makishima, Tatsuhiro Sakamoto, Aya Sawa, Hiroko Bando, Daisuke Kaji, Takeshi Sugio, Koji Kato, Koichi Akashi, Kosei Matsue, Joaquim Carreras, Naoya Nakamura, Ayako Suzuki, Yutaka Suzuki, Ken Ito, Hiroyuki Shiiba, Shigeru Chiba, Mamiko Sakata‐Yanagimoto
Abstract
Abstract 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.