Tony Kurian, MD, Oncology Fellow at H. Lee Moffitt Cancer Center & Research Institute speaks about the ASCO 2021 Abstract – Using tissue microarray to detect inflammasome signaling components that contribute to the pathogenesis of myelodysplastic syndrome.
Link to Abstract:
https://meetinglibrary.asco.org/record/196283/abstract
Background:
Abnormal maturation, inefficient hematopoiesis, cytopenia, and the development of acute myeloid leukemia are all symptoms of myelodysplastic syndromes (MDS). The etiology of MDS is complex, and it may be connected to innate immunological activation that converges on the NLRP3 inflammasome to cause pyroptosis, a caspase-1-dependent cell death. Both cell-extrinsic stimuli, such as S100A9, the TLR4, and CD33 ligand, and cell-intrinsic danger signals, such as caspase-1, which activates IL1b and beta-catenin, cause cell death and proliferation, resulting in maturation and differentiation blocks, activate the inflammasome. EYA2 has also been proposed as an inflammasome activator, whilst cPLA2 has been proposed as an inhibitor. The goal of this research is to see if immunohistochemistry (IHC) can be used to measure inflammasome component expression.
Methods:
Prior to the start of the trial, an IRB protocol was authorized. We found 43 low-risk MDS individuals retrospectively. MDS bone marrow biopsy samples were used to create a tissue microarray (TMA) (2-3 representative cores per sample). After each antibody was validated, IHC was used to evaluate IL-1, S100A9, EYA2, cPLA2, beta-catenin, and TLR4 expression. Two hematopathologists independently assessed IHC expression by generating scores (product of staining intensity x percent expression). The Spearman correlation estimate was used to compare IHC expression. The Kruskal-Wallis test, Spearman correlation, and Logrank test were used to correlate demographic and clinical data with IHC expression.
Results:
Patients ranged in age from 72 to 67 years old, with 47 percent having MDS-MLD, 35 percent having MDS-RS, 14 percent having MDS-SLD, 2 percent having MDS del5q, and 2 percent having MDS-U. IL-1 expression was found to be correlated with beta-catenin expression, with a r = 0.42, 95 percent CI 0.115 to 0.658 (p = 0.007). Between IL-1 and cPLA2, r = 0.30 (p = 0.067), S100A9 and cPLA2, r = 0.31 (p = 0.052), and S100A9 and EYA2, r = 0.31 (p = 0.057), there was a tendency toward significance. The percentage of EYA2 expression was associated with the number of blasts (r = 0.425, p = 0.008). These antigens’ IHC expression had no relationship with WHO MDS subclassification, IPSS, R-IPSS, disease progression, or survival (p > 0.05).
Conclusions:
TMA-based IHC labeling of inflammasome activators may provide for a better understanding of the molecular processes involved in MDS pathogenesis. The expression of antigens known to be elevated downstream of NLRP3 inflammasome activation was shown to be linked. Furthermore, greater EYA2 expression was linked to a higher blast count. To further clarify the etiology of MDS and discover possible targetable indicators for innovative treatment options, a future study will analyze expression patterns between normal, low risk MDS, and high risk MDS samples and connect these findings with clinical outcome data.