Tili Esmerina, Commisso Teresa L, Balatti Veronica, Michaille Jean-Jacques, Nuovo Gerard J, Croce Carlo M
Department of Anesthesiology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH 43210.
Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2422615122. doi: 10.1073/pnas.2422615122. Epub 2025 Apr 18.
Elevated levels in B cell malignancies, such as CLL and DLBCL, correlate with increased aggressiveness of the disease. We recently reported that, in two different mouse models of -driven B cell malignancy, targets and down-regulates transcripts encoding ICOSL, the ligand for the Inducible T cell costimulator (ICOS), thereby impairing the capacity of T lymphocytes to recognize and eliminate malignant cells. In this report, we extend our previous findings to Human by showing that levels negatively correlate with those of both ICOSL and MHC-I in samples from DLBCL patients. We present evidence of reducing the levels of transcripts in ABC, but not in GCB primary tumors (PTs) and cell lines (CLs). In contrast, there was no evidence of targeting transcript levels in both types of DLBCLs. Nevertheless, and MHC-I levels inversely correlated in DLBCLs samples, suggesting the existence of indirect regulatory effects of . There was also evidence of dose-dependent effects at low levels. Altogether, our findings indicate that the deficiency of both ICOSL and MHC-I activity, driven by high levels of , may be causative in the failure of the host immune system to recognize and eliminate malignant B cells.
在B细胞恶性肿瘤（如慢性淋巴细胞白血病和弥漫性大B细胞淋巴瘤）中，水平升高与疾病侵袭性增加相关。我们最近报道，在两种不同的由驱动的B细胞恶性肿瘤小鼠模型中，靶向并下调编码可诱导T细胞共刺激分子（ICOS）的配体ICOSL的转录本，从而损害T淋巴细胞识别和消除恶性细胞的能力。在本报告中，我们通过显示弥漫性大B细胞淋巴瘤患者样本中的水平与ICOSL和MHC-I的水平呈负相关，将我们之前的发现扩展到了人类。我们提供了证据表明在ABC中降低了转录本水平，但在GCB原发性肿瘤（PTs）和细胞系（CLs）中没有。相反，没有证据表明在两种类型的弥漫性大B细胞淋巴瘤中靶向转录本水平。然而，在弥漫性大B细胞淋巴瘤样本中，和MHC-I水平呈负相关，表明存在的间接调节作用。在低水平时也有剂量依赖性效应的证据。总之，我们的研究结果表明，高水平驱动的ICOSL和MHC-I活性缺乏可能是宿主免疫系统无法识别和消除恶性B细胞的原因。
