Xue Li

T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. In this review, we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells in fighting cancers.

Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA–DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA–DOTA-Gd copolymers displayed 2–3-fold increased relaxivity (r1 value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA–DOTA-Gd copolymer might have greater benefits for the foreground.

The efficacy and biocompatibility of nanoscale magnetic resonance imaging (MRI) contrast agents depend on optimal molecular structures and compositions. Gadolinium [Gd(III)] based dendritic macromolecules with well-defined and tunable nanoscale sizes are excellent candidates as multivalent MRI contrast agents. Here, we propose a novel alternate preparation of biodegradable hyperbranched polymer-gadolinium conjugates via a simple strategy and report potentially efficient and biocompatible nanoscale MRI contrast agents for cancer diagnosis. The enzyme-responsive hyperbranched poly(oligo-(ethylene glycol) methacrylate)-gadolinium conjugate (HB-POEGMA-Gd) was prepared via one-step reversible addition-fragmentation chain transfer (RAFT) polymerization and Gd(III) chelating, and the cRGDyK functionalized polymer (HB-POEGMA-cRGD-Gd) was obtained via click chemistry. By using an enzyme similar to lysosomal cathepsin B, hyperbranched conjugates of high molecular weights (MW) (180 and 210 kDa) and nanoscale sizes (38 and 42 nm) were degraded into low MW (25 and 30 kDa) and smaller products (4.8 and 5.2 nm) below the renal threshold. Conjugate-based nanoscale systems had three-fold more T1 relaxivity compared to clinical agent diethylenediaminepentaacetic acid (DTPA)-Gd. Animal studies with the nanoscale system offered greater tumor accumulation and enhanced signal intensity (SI) in mouse U87 tumors of which the greatest activity was conferred by the cRGDyK moiety functionalized hyperbranched conjugate. In vitro cytotoxicity, hemocompatibility and in vivo toxicity studies confirmed no adverse events. This design strategy for multifunctional Gd(III)-labeled biodegradable dendritic macromolecules may have significant potential as future efficient, biocompatible polymeric nanoscale MRI diagnostic contrast agents for cancer.

Exosomal microRNAs (miRNAs) are considered as potential stable biomarkers in many types of human cancer, but investigations of plasma-derived exosomal miRNAs in oral squamous cell carcinoma (OSCC) are still lacking. The aim of this study is to evaluate the diagnostic and prognostic values of exosomal miR-130a in OSCC patients. Exosomes were isolated from plasma samples which were collected from 184 OSCC patients before surgery and 196 healthy individuals. Primary OSCC and paired adjacent noncancerous tissues were also obtained from 47 OSCC patients. The expression levels of miR-130a were analyzed by quantitative real-time PCR (qRT-PCR). Our results showed that the expression levels of exosomal miR-130a were significantly higher in OSCC patients than those of the healthy controls ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mi>p</a:mi> <a:mo>&lt;</a:mo> <a:mn>0.0001</a:mn> </a:math> ). Also, the expression of miR-130a was also significantly upregulated in OSCC tissues compared with paired adjacent noncancerous tissues ( <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"> <c:mi>p</c:mi> <c:mo>&lt;</c:mo> <c:mn>0.0001</c:mn> </c:math> ). A significant positive correlation was found between exosomal miR-130a and tissue miR-130a levels. Receiver operating characteristic (ROC) analyses yielded an AUC value of 0.812 in discriminating OSCC patients from healthy controls. Furthermore, high levels of exosomal miR-130a were associated with the late T-stage ( <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"> <e:mi>p</e:mi> <e:mo>=</e:mo> <e:mn>0.024</e:mn> </e:math> ), advanced TNM stage ( <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"> <g:mi>p</g:mi> <g:mo>=</g:mo> <g:mn>0.003</g:mn> </g:math> ), and poorly differentiated OSCC ( <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"> <i:mi>p</i:mi> <i:mo>=</i:mo> <i:mn>0.013</i:mn> </i:math> ). Patients with high exosomal miR-130a expression had significantly worse 3-year overall survival (OS) and recurrence-free survival (RFS). Multivariate analysis indicated that exosomal miR-130a was an independent prognostic factor for OS ( <k:math xmlns:k="http://www.w3.org/1998/Math/MathML" id="M6"> <k:mi>p</k:mi> <k:mo>=</k:mo> <k:mn>0.001</k:mn> </k:math> ) and RFS ( <m:math xmlns:m="http://www.w3.org/1998/Math/MathML" id="M7"> <m:mi>p</m:mi> <m:mo>=</m:mo> <m:mn>0.003</m:mn> </m:math> ). Our results suggest that exosomal miR-130a may serve as a promising diagnostic and prognostic biomarker for OSCC patients.

With the development of multifunctional imaging, gadolinium (Gd)-bearing inorganic nanoparticles (NPs), which were doped with trivalent lanthanide (Ln3+), have been applied in magnetic resonance imaging (MRI) and optical imaging owing to their high payload of Gd3+ ions and specific optical characteristics. In this study, we chose GdVO4 codoped with Eu3+ and Bi3+ as the host material to generate a highly efficient contrast agent (CA) for MRI and long-term luminescence imaging. The new CA emits strong and stable luminescence because of its strong characteristic emissions, resulting from the energy-transfer process from the vanadate groups (VO43–) to the Eu3+ and Bi3+ dopants. Additionally, these NPs provided conspicuous T1 and T2 relaxation time-shortening characteristics, which result in MRI enhancement. GdVO4:Eu3+,Bi3+ NPs were tested on liver tumor-bearing nude mice, and showed improved liver tumor contrast in T2-weighted MR images (T2WI). The dual-modal imaging probe exhibited no cytotoxicity or organ toxicity, reflecting its excellent biocompatibility. Thus, GdVO4:Eu3+,Bi3+ has the potential to be used for bioassays in vitro and liver tumor targeting in vivo. The results reveal the great promise of using the designed GdVO4:Eu3+,Bi3+ NPs as luminescent and MRI dual-mode bioprobes for clinical bioimaging applications.