Enhancements in the diagnostic capabilities using host biomarkers are currently much needed where sensitivity and specificity issues plague the diagnosis of Hand, Foot and Mouth Disease (HFMD) in pediatrics clinical samples. We investigated miRNome profiles of HFMD saliva samples against healthy children and developed miRNA-based diagnosis models. Our 6-miRNA scoring model predicted HFMD with an overall accuracy of 85.11% in the training set and 92.86% in the blinded test set of Singapore cohort. Blinded evaluation of the model in Taiwan HFMD cases resulted in 77.08% accuracy with the 6-miRNA model and 68.75% with the 4-miRNA model. The strongest predictor of HFMD in all of the panels, hsa-miR-221 was found to be consistently and significantly downregulated in all of our HFMD cohorts. This is the first study to prove that HFMD infection could be diagnosed by circulating miRNAs in patient's saliva. Moreover, this study also serves as a stepping stone towards the future development of other infectious disease diagnosis workflows using novel biomarkers.
CAR-T cells utilize TCR signaling cascades and the recognition functions of antibodies. CAR-T technology has achieved significant success in treatment of certain, primarily liquid, cancers. Nonetheless, many challenges hinder the development of this therapy, for example the efficacy for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, and how it may differ from TCR signaling. To dissect CAR signaling, CAR and TCR targeting the same antigen were compared directly. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. Surprisingly, we identified a non-canonical CAR signaling triggered in the absence of SRC family kinase (SFK) LCK, which is essential for TCR signaling. We show that LCK-deficient CAR-T cells are strongly signaled through CAR and have a better in vivo efficacy because of reduced exhaustion phenotype and enhanced induction of memory. This non-canonical signaling of CAR-T cells provides new insight into the initiation of TCR and CAR signaling as well as important clinical implications for improvement of CAR function. Supported by grants from Singapore Ministry of Health’s National Medical Research Council: OFIRG19nov-0066; and Ministry of Education, NUHSRO/2020/110/T1/SEED-MAR/06, and NUS ILO TAP Grant: TAP2002019-04-25. LW, QW and JL were supported by research scholarships from Yong Loo Lin School of Medicine.
Background Chimeric antigen receptor (CAR) T therapy has shown remarkable success in treating liquid tumours but current approved therapies rely on autologous T cells which are expensive, difficult to manufacture and not readily available for patients whose disease progress rapidly. The production of safe and effective allogeneic CAR-T cells is needed to increase accessibility of CAR-T therapy and broaden its application. The main approach to generate allogeneic CAR-T therapy is by disrupting T cell receptor (TCR) expression to minimize Graft-versus-Host Disease (GVHD) mediated through the TCR of donor cells against the recipient's major histocompatibility complex (MHC). However, the TCR disruption approach has shown limited persistence in vivo [1] and in clinical trials [2] unlike the long term durability of autologous CAR-T cells.Here, we propose a novel platform for allogeneic CAR-T therapy that retains the TCR but inhibits TCR signalling by knocking out the Lymphocyte-specific protein tyrosine kinase (LCK)a well-established kinase for proximal TCR activation. This builds on the discovery that our second generation CD28-CAR can be activated independently of LCK unlike the endogenous TCR.
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