Serum Tsrna Can be Used As a Biomarker of the Activation States of T Cells for Early Detection of GvHD after Allogeneic Stem Cell Transplantation

Background

Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. However, as a common complication after transplantation, GvHD remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. tRNA-derived small non-coding RNA (tsRNA) is a class of newly identified small noncoding RNA (sncRNA), usually ~30 nucleotides (nt) in length. tsRNA was found to be highly enriched in vertebrate serum as remarkably stable forms, suggesting a promising role of serum tsRNAs as diagnostic biomarkers for human diseases and actively involved in starvation, oxidative stress, hypoxia, and other adverse conditions. Here, by employing small non-coding RNA sequencing on serum of patients who underwent HSCT, we presented the landscape of tsRNA profiles and showed the difference in patients with GvHD and non-GvHD, which can be further used as fingerprints for early detection of GvHD after allo-HSCT.

Methods

In this retrospective cohort study, two cohorts were incorporated and serum samples were prospectively collected before drug treatment (-7 day), before stem cell transfusion after drug treatment (-1 day), the 7th day after stem cell transfusion (+7 day), the 14th day after stem cell transfusion (+14 day), and the 28th day after stem cell transfusion (+28 day) if possible, namely 1) the auto-transplantation cohort: 50 serum samples in total, including 10 patients undergoing the auto-transplantation.2) the allogeneic transplantation cohort: 149 serum samples in total, including 35 patients undergoing the auto-transplantation. Serum RNA was extracted and measured by small noncoding RNA sequencing, RT-qPCR, and northern blot.

Results

By employing small RNA sequencing, we found significant differences in tsRNA after hematopoietic stem cell transplantation, especially in GvHD and non-GvHD groups. In the non-GvHD group, tsRNA usually goes through a low (+7d) - high (+14d) - low (+28d) express pattern. However, in the GvHD group, tsRNA still maintains high-level expression at +28d of allo-HSCT, which presents a low (+7d) - high (+14d) - high (+28d) express pattern. Additionally, by simulating T cells in vitro, we found that T cells secrete a large amount of functionally tsRNA into the extracellular space after activation and those tsRNAs can induce cell apoptosis. Taken together, It suggests that tsRNA-mediated epigenetic information may be involved in regulating the occurrence and development of GvHD after allo-HSCT, and can serve as specific diagnostic markers.

Conclusions

The express pattern of serum tsRNA at 14d to 28d after allogeneic stem cell transplantation could represent the activation states of T cells and can be fingerprinted for early detection of GvHD after allo-HSCT.

No relevant conflicts of interest to declare.