Abstract
Abstract
Background: Acute lymphoblastic leukemia (ALL) is the most common type of childhood malignancy. Despite all the improvements in ALL treatment, cancer relapse remains a major dilemma. Immune checkpoint inhibitors are promising agents that are being evaluated in ALL clinical trials. The overall aim of our study is to evaluate the expression status of immune checkpoint genes in pediatric ALL patients as prognostic factors for the time of relapse and identify possible targets for immunotherapy.
Methods: The expression of 21 regulatory immune checkpoint genes was extracted from two microarray datasets of precursor-B-ALL patients (Hogan et al. dataset (GSE28460) included 49 patients and Staal et al. dataset (GSE18497) contained 27 patients). The microarray data were run using the robust multichip average normalization method in RStudio (1.3.959). A 36 month-cutoff was determined to stratify patients into two groups, early relapse (< 36 months) and late relapse (≥ 36 months). The two datasets were normalized to a reference group (late relapse), then combined. The significant differentially expressed genes between the two groups were detected using Student's t-test. An expression score was generated for each patient based on the expression of the significant differentially expressed genes. Survival analysis and Pearson's correlation were performed to assess the impact of significant genes on the time of relapse.
Results: 19 out of the 21 genes were downregulated in early relapsing patients compared to the late relapsing group, seven of which were statistically significant; BTLA4, KIR3DS, PDCD1, TIGIT, HAVCR, CTLA4, TNFRSF9. The expression of those seven genes was significantly associated with the time of relapse ( r = 0.381, P = 0.0007). Patients with a low expression profile of the significant differentially expressed genes were 2.3 times more likely to relapse early (CI 1.434-3.713, P = < 0.0001).
Conclusion: The expression of immune checkpoint genes is significantly associated with the prognosis of ALL patients. BTLA4, KIR3DS, PDCD1, TIGIT, HAVCR, CTLA4, and TNFRSF9 might be prognostic factors for the time of relapse. Immunotherapy might be beneficial to the late relapsing patients where immune checkpoint genes were upregulated. The study was funded by the deputyship for Research and Innovation, Ministry of Education, Saudi Arabia (DRI-KSU-1273).
Citation Format: Basil Jamal Alotaibi, Razan Saad Alshahrani, Munirah Abdulaziz Alkathiri, Ali Mohammed Alqasem, Basil Nasser Alamri, Ali Rashed Alhoshani, Moureq Rashed Alotaibi, Khalid Ahmed Alhazzani, Homood Moqbel As Sobeai. Low expression of immune checkpoint genes is significantly associated with early relapse in pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3031.