Increased co-expression of CTLA4/LAG3 predicted adverse clinical outcomes in patients with T-cell malignancies

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.