Increased co-expression of CTLA4/LAG3 predicted adverse clinical outcomes in patients with T-cell malignancies
Peipei Wang, Qinghua Cai, Xueting Peng, Cong Dai, Jinyi Liu, Weini Li, Runyi Lin, Ying Liu, Shiyi Pan, Yuping Zhang, Caixia Wang, Cunte Chen
Abstract
The application of immune checkpoint blockers (ICBs) in immunotherapy has markedly improved the prognosis for patients with solid tumors and B-cell lymphomas, and it holds promise as a novel therapeutic approach for T-cell malignancies, such as T-cell lymphoma (TCL) and T-cell acute lymphoblastic leukemia (T-ALL). However, the use of expression patterns of inhibitory immune checkpoints (IICs) for fully evaluating the clinical outcomes of patients with TCM remains to be fully elucidated. This study employed bulk RNA-seq data sourced from 162 patients with TCL in the GSE58445 dataset, alongside quantitative real-time polymerase chain reaction data obtained from peripheral blood samples of 33 patients with TCL and 36 patients with T-ALL at our clinical center (GZFPH dataset) to explore the prognostic significance of IICs. The results revealed a significant association between increased expression levels of the IICs cytotoxic T lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene-3 (LAG3) and programmed cell death ligand 2 (PD-L2) and unfavorable outcomes in terms of both overall survival (OS) and relapse-free survival (RFS) among patients diagnosed with TCL and T-ALL. Among them, CTLA4 and LAG3 was the best combination for predicting the OS and RFS of patients with TCL and T-ALL ( P < 0.05). A nomogram model established with CTLA4, LAG3 and prognostic clinical information could individually visualize the 1 to 5-year OS rates for patients with TCM. Notably, the standard risk stratification method could be surpassed by the novel risk stratification method utilizing the nomogram model, enabling a more accurate prediction of OS and RFS for patients with TCM. In particular, the single-cell RNA-seq data of patients with TCL in the GSE165623 dataset suggested that CTLA4 and LAG3 were mainly elevated in the cancer cells and intermediate exhausted CD8+ T cells (CD8_Ex_inter) of TCL, respectively. In summary, elevated CTLA4, LAG3 and PD-L2 expression levels emerged as potent predictors of adverse clinical outcomes for patients with TCM. The concurrent upregulation of CTLA4 and LAG3 could potentially serve as a novel immune biomarker, facilitating the development of dual ICBs tailored specifically for TCM. • High expression of CTLA4, LAG3 and PD-L2 predicted adverse outcomes for TCM patients. • CTLA4 and LAG3 was the best combination for predicting the OS and RFS of TCM patients. • CTLA4 and LAG3 serve as immune biomarkers for risk stratification. • CTLA4 and LAG3 were mainly elevated in the cancer cells and intermediate exhausted CD8+ T cells of TCL, respectively.