During an acute infection, serum levels of certain proteins will be increased dramatically at the early stage of the infection, which are so-called acute phase proteins (APPs). Among them, C-reactive protein (CRP) and Serum Amyloid A (SAA) are two major APPs in humans and therefore they have long been used as clinical biomarkers to monitor the inflammation and the outcome of therapy. However, the physiological function of CRP and SAA remains to be better characterized. In our study, we have shown that CRP can functionally activate Fc receptors pathways, particularly FcγRs and FcαRI (CD89), resulting in the phagocytosis of microbial pathogens and cytokine secretion, such as IL6, and IL8. The ability of CRP to activate FcγRs and FcαRI defines a novel function for acute phase proteins in inflammatory responses involving neutrophils and macrophages and also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors. Furthermore, SAA was shown to be able to bind Gram-positive bacteria. We have now determined the X-ray structure of SAA at 2.7Å resolution. The natural hexameric SAA structure revealed a dimeric architecture arranged as two trimers. We also discovered that SAA hexamer could undergo a transition to monomers that are able to bind and activate Toll-like receptor 2 and 4. Taken together, our studies highlighted CRP and SAA as the powerful first lines of host immune defense during acute infection.
Complete regression of cancer has been observed in a subset of patients following adoptive T-cell transfer (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TIL). However, the low success rate of ACT presents a great challenge to broader clinical application. To provide a rational approach to TIL-based immunotherapy, we developed a three-pronged approach to comprehensively evaluate clinically relevant traits of TIL-TCR. We applied the approach to a successful case of ACT where regression was observed against tumors carrying the hotspot mutation KRAS-G12D. We show that only G12D mutant peptides (a nonamer and a decamer) but not wildtype peptides can be presented by HLA-C*08:02. Structurally, the mutated Asp formed a salt bridge necessary for HLA-C binding. Therapeutic TCRs exhibited high affinity anti-tumor binding both in solution and on reconstituted T-cells. The nonamer G12D is recognized by multiple TCR9 through conserved contacts on their shared CDR2β and CDR3α, allowing CDR3β variation to generate an oligoclonal response. The decamer G12D is recognized by TCR10 through an induced peptide conformation. Interestingly, the antigen binding affinities of these TIL-TCR inversely correlated with their persistence in vivo. Importantly, the successful ACT contained TCRs specific for two non cross-reactive conformationally distinct tumor epitopes. We conclude that successful ACT requires high affinity oligoclonal TCRs with specificity for multiple antigens to optimize tumor clearance and in vivo persistence. This approach has the potential to transform current trial and error aspect of TIL-based immunotherapy to a rational selection of TCRs with optimal therapeutic properties.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.