CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients
Journal of Hematology & Oncology volume 14, Article number: 90 (2021)
The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.
To the Editor,
Multiple myeloma (MM) is still an incurable hematological malignancy, as most of MM patients eventually relapse or become refractory [1, 2]. Strikingly, the CAR-T cell therapy has achieved satisfactory efficacy in patients with relapsed or refractory MM in recent years . However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics . To explore the potential biomarkers in plasma, we uniquely imported metabolomics analytic techniques and examined the profile changes of metabolites and lipids in plasma from 17 relapsed or refractory MM patients post-CAR-T therapy (Fig. 1a). The clinical characteristics of 17 participants are presented in Additional file 1: Table S1.
We first detected the differential metabolites in CRS group including participants with CRS within the first week post-infusion and without CRS at day 30 post-infusion (Additional file 1: Fig. S1) and comparative efficacy group (CE group) including participants with remission and non-remission at day 30 post-infusion by UPLC-MS in positive electrospray ionization (ESI+) mode (Additional file 2: Table S2, S3). The representative total ion chromatograms (TIC) for all participants demonstrated the well separation of metabolites in plasma (Fig. 1b). Subsequently, the principal component analysis (PCA) and the orthogonal partial least squares discriminant analysis (OPLS-DA) (Additional file 2: Fig. S2)showed significant differences among samples from CRS group (Fig. 1c, d) or CE group (Fig. 1f, g). By measuring the variable importance, 19 and 21 substances were distinguished in CRS group (Fig. 1e) and CE group (Fig. 1h), respectively. After matching KEGG modules, 5 and 7 differential metabolites were identified from the two comparisons, respectively, shown as a heatmap (Fig. 1i, j). Oxidized glycerophosphocholine (Ox-GPC) is PAF-like molecule combining with PAF receptor . Platelet-activating factor (PAF), known as 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine , is produced through remodeling or de novo pathway involved in different biological pathways of inflammation , tumor cell growth , and invasion [9, 10]. Compared to the patients without CRS at day 30, the plasma level of GPC was significantly decreased in patients with CRS (Fig. 1k), indicating that the activation of GPC oxidative phosphorylation and the intensification of PAF synthesis were associated with CRS. Intriguingly, Lysophosphatidylcholine (LPC), as an intermediate in remodeling pathway to form PAF with the addition of an acetyl group, is catalyzed by LPC acyltransferase (LPCAT) . The plasma levels of LPC(16:0) and palmitoylcarnitine were significantly increased in relieved participants from CE group (Fig. 1l, m).
We further conducted targeted metabolomics to explore LPCs volume, and as shown in Fig. 2a, disorderedly metabolic pathways were involved in PAF synthesis . Moreover, the area under receiver operating characteristic (ROC) curve of LPC(16:0) was 0.9833, suggesting that LPC could serve as a potential plasma biomarker for prognosis of relapsed or refractory MM (Fig. 2b). Then, to validate reliable plasma biomarkers for prognosis of CAR-T therapy (Additional file 3: Table S4), we detected TIC, PCA, and OPLS-DA (Additional file 3: Fig. S3) of lipidomic profiling in CE group represented in Fig. 2c–e, respectively. LPC(O-24:0), LPC(20:4) and LPC(16:1/0:0), significantly heightened in relieved participants at day 30 post-CAR-T therapy among 44 differential lipids (Fig. 2f–i). Heatmap showed marked elevation of the three LPCs compared with top 20 differential lipids (Fig. 2j). In addition, LPCAT1, one of LPCAT family members, is crucial for lipid droplet remodeling and LPC metabolism . Therefore, we assessed the gene expression of LPCAT1 in normal people (NP), MGUS and MM bone marrow plasma cells based on GEP dataset. The LPCAT1 mRNA was remarkably increased in MM patients compared with MGUS and NP (p = 0.0332; Fig. 2k). Furthermore, unlike other members in LPCAT family (Additional file 4: Fig. S4), higher LPCAT1 expression was associated with poor overall survival (OS) in MM patients (TT2, GSE2658) (p = 0.0378; Fig. 2l). This finding was also verified in other two independent cohorts, HOVON-65 clinical trial (p = 0.0052; Fig. 2m) and the APEX phase III clinical trial (p = 0.0003; Fig. 2n). Additionally, we found that LPCAT1 mRNA was significantly increased in relapsed MM patients compared with newly diagnosed patients from TT2 cohort (GSE38627) (p = 0.0065; Fig. 2o).
Our study demonstrated that CAR-T therapy could inhibit the remodeling pathway of PAF synthesis via inactivating LPCAT1 and lead to the elevation of plasma LPCs. We also propose that LPCAT1 may act as an oncogene in MM, which is available to be targeted in clinics particularly in CAR-T therapy. Collectively, targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.
Availability of data and materials
All supporting data are included in the manuscript and supplemental files. Additional data are available upon reasonable request to the corresponding author.
Chimera antigen receptor
Cytokine release syndrome
Gene expression profiling
Total ion chromatograms
Principal component analysis
Orthogonal partial least squares discriminant analysis
Variable importance in the projection
Kyoto encyclopedia of genes and genomes
Receiver operating characteristic
Monoclonal gammopathy of undetermined significance
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We thank Prof. Hongbo Wang, Prof. Jinjun Shan and Dr. Zhihua Song for providing equipment support. We thank Caihong Li, Zichen Luo, Weichen Xu, Yu He and Yang zhou for providing technical support.
This work was supported by National Key R&D Program of China (No. 2020YFA0509400); Natural Science Foundation of Jiangsu Province BK20200097 (to CG); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine).
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All participants provided written informed consent in accordance with the approval of the ethics committee of the Affiliated Hospital of Nantong University (2018-K007) in agreement with the Declaration of Helsinki. Institutional approval was not required to publish this manuscript.
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Ke, M., Kang, L., Wang, L. et al. CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients. J Hematol Oncol 14, 90 (2021). https://doi.org/10.1186/s13045-021-01101-6