The future of cancer vaccines against colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the second most lethal malignancy worldwide. Immune checkpoint inhibitors (ICIs) benefit only 15% of patients with mismatch repair-deficient/microsatellite instability (dMMR/MSI) CRC. The majority of patients are not suitable due to insufficient immune infiltration. Cancer vaccines are a potential approach for inducing tumor-specific immunity within the solid tumor microenvironment. AREA COVERED: In this review, we have provided an overview of the current progress in CRC vaccines over the past three years and briefly depict promising directions for further exploration. EXPERT OPINION: Cancer vaccines are certainly a promising field for the antitumor treatment against CRC. Compared to monotherapy, cancer vaccines are more appropriate as adjuvants to standard treatment, especially in combination with ICI blockade, for microsatellite stable patients. Improved vaccine construction requires neoantigens with sufficient immunogenicity, satisfactory HLA-binding affinity, and an ideal delivery platform with perfect lymph node retention and minimal off-target effects. Prophylactic vaccines that potentially prevent CRC carcinogenesis are also worth investigating. The exploration of appropriate biomarkers for cancer vaccines may benefit prognostic prediction analysis and therapeutic response prediction in patients with CRC. Although many challenges remain, CRC vaccines represent an exciting area of research that may become an effective addition to current guidelines.

Particle-Based Artificial Antigen-Presenting Cell Systems for T Cell Activation in Adoptive T Cell Therapy.

T cell-based adoptive cell therapy (ACT) has emerged as a promising treatment for various diseases, particularly cancers. Unlike other immunotherapy modalities, ACT involves directly transferring engineered T cells into patients to eradicate diseased cells; hence, it necessitates methods for effectively activating and expanding T cells in vitro. Artificial antigen-presenting cells (aAPCs) have been widely developed based on biomaterials, particularly micro- and nanoparticles, and functionalized with T cell stimulatory antibodies to closely mimic the natural T cell-APC interactions. Due to their vast clinical utility, aAPCs have been employed as an off-the-shelf technology for T cell activation in FDA-approved ACTs, and the development of aAPCs is constantly advancing with the emergence of aAPCs with more sophisticated designs and additional functionalities. Here, we review the recent advancements in particle-based aAPCs for T cell activation in ACTs. Following a brief introduction, we first describe the manufacturing processes of ACT products. Next, the design and synthetic strategies for micro- and nanoparticle-based aAPCs are discussed separately to emphasize their features, advantages, and limitations. Then, the impact of design parameters of aAPCs, such as size, shape, ligand density/mobility, and stiffness, on their functionality and biomedical performance is explored to provide deeper insights into the design concepts and principles for more efficient and safer aAPCs. The review concludes by discussing current challenges and proposing future perspectives for the development of more advanced aAPCs.

A copper-platinum nanoplatform for synergistic photothermal and chemodynamic tumor therapy via ROS outburst and GSH exhaustion.

A multifunctional nanoplatform is obtained by modifying copper hexacyanoferrate (Cu-HCF) nanozyme with hyaluronic acid (HA) and further loading platinum (Pt) nanoparticles. This Cu-HCF-HA@Pt platform shows peroxidase-like and glutathione oxidase-like dual-enzyme catalytic activities and photothermal properties, enabling synergistic chemodynamic and photothermal tumor therapy. HA binds to the CD44 receptor, which is highly expressed on the exterior surface of tumor cells, endowing the nanoplatform with tumor specificity. Cu-HCF-HA@Pt catalyzes the decomposition of H2O2 to produce abundant hydroxyl radicals within tumor cells, increasing intracellular oxidative stress levels and inducing tumor cell apoptosis. Meanwhile, Cu-HCF-HA@Pt catalyzes the conversion of intracellular reduced glutathione (GSH) to oxidized glutathione, resulting in GSH exhaustion. The conversion of CuII to CuI in Cu-HCF via a Fenton-like reaction can improve the peroxidase-like property of Cu-HCF-HA@Pt. After the probe is targeted to the tumor site, irradiation by an 808 nm near-infrared laser causes local heating and brings about photothermal tumor apoptosis when reaching 45 °C. The prepared Cu-HCF-HA@Pt combines nanozyme-catalyzed therapy with photothermal therapy to induce apoptosis in tumor cells.

Effect of Fragment 1 on the Binding of Epigallocatechin Gallate to the PD-L1 Dimer Explored by Molecular Dynamics.

Blocking the interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) by directly targeting the PD-L1 dimer has emerged as a hot topic in the field of cancer immunotherapy. Epigallocatechin gallate (EGCG), a natural product, has been demonstrated binding to the PD-L1 dimer in our previous study, but has a weaker binding capacity, moreover, EGCG is located at the end of the binding pocket of the PD-L1 dimer. The inhibitor fragment 1 (FRA) lies at the other end. So, we proposed that the introduction of FRA might be able to improve the binding ability. To illuminate this issue, molecular dynamics (MD) simulation was performed in the present study. Binding free energy calculations show that the binding affinity is significantly increased by 17 kcal/mol upon the introduction of FRA. It may be due to the energy contributions of emerging key residues ATyr56, AMet115, BTyr123, AIle54 and the enhanced contributions of initial key residues ATyr123 and BVal68. Binding mode and non-bonded interaction results indicate that FRA_EGCG (EGCG in combination with FRA) binds to the C-, F- and G-sheet of the PD-L1 dimer. Importantly, the introduction of FRA mainly strengthened the nonpolar interactions. The free energy landscape and secondary structure results further show that FRA_EGCG can interact with the PD-L1 dimer more stably. These data demonstrated here provide the theoretical basis for screening two or more natural products with additive inhibitory effect on this pathway and therefore exerting more effective anticancer immunity.

Clinical status and future prospects of single-incision robotic-assisted surgery: a review.

Since the advent of conventional multiport laparoscopic surgery, the prosperity of minimally invasive surgery has been thriving on the advancement of endoscopic techniques. Cosmetic superiority, recovery benefits, and noninferior surgical outcomes weigh single-incision laparoscopic surgery as a promising modality. Although there are surgical challenges posed by steep learning curve and technological difficulties, such as instruments collision, triangulation loss and limited retraction, the establishment of robotic surgical platform as a solution to all is inspiring. Furthermore, with enhanced instrument maneuverability and stability, robotic ergonomic innovations adopt the advantages of single-incision laparoscopic surgery and surmount its recognized barriers by introducing a novel combination, single-incision robotic-assisted surgery. As was gradually diffused in general surgery and other specialties, single-incision robotic-assisted surgery manifests privileges in noninferior clinical outcomes an satisfactory cosmetic effect among strictly selected patients, and has the potential of a preferable surgical option for minimally invasive surgery.

Identification and verification of a prognostic signature based on a miRNA-mRNA interaction pattern in colon adenocarcinoma.

The expression characteristics of non-coding RNA (ncRNA) in colon adenocarcinoma (COAD) are involved in regulating various biological processes. To achieve these functions, ncRNA and a member of the Argonaute protein family form an RNA-induced silencing complex (RISC). The RISC is directed by ncRNA, especially microRNA (miRNA), to bind the target complementary mRNAs and regulate their expression by interfering with mRNA cleavage, degradation, or translation. However, how to identify potential miRNA biomarkers and therapeutic targets remains unclear. Here, we performed differential gene screening based on The Cancer Genome Atlas dataset and annotated meaningful differential genes to enrich related biological processes and regulatory cancer pathways. According to the overlap between the screened differential mRNAs and differential miRNAs, a prognosis model based on a least absolute shrinkage and selection operator-based Cox proportional hazards regression analysis can be established to obtain better prognosis characteristics. To further explore the therapeutic potential of miRNA as a target of mRNA intervention, we conducted an immunohistochemical analysis and evaluated the expression level in the tissue microarray of 100 colorectal cancer patients. The results demonstrated that the expression level of POU4F1, DNASE1L2, and WDR72 in the signature was significantly upregulated in COAD and correlated with poor prognosis. Establishing a prognostic signature based on miRNA target genes will help elucidate the molecular pathogenesis of COAD and provide novel potential targets for RNA therapy.

Molybdenum Disulfide-Integrated Iron Organic Framework Hybrid Nanozyme-Based Aptasensor for Colorimetric Detection of Exosomes.

Tumor-derived exosomes are considered as a potential marker in liquid biopsy for malignant tumor screening. The development of a sensitive, specific, rapid, and cost-effective detection strategy for tumor-derived exosomes is still a challenge. Herein, a visualized and easy detection method for exosomes was established based on a molybdenum disulfide nanoflower decorated iron organic framework (MoS2-MIL-101(Fe)) hybrid nanozyme-based CD63 aptamer sensor. The CD63 aptamer, which can specifically recognize and capture tumor-derived exosomes, enhanced the peroxidase activity of the hybrid nanozyme and helped to catalyze the 3,3',5,5'-tetramethylbenzidine (TMB)-H2O2 system to generate a stronger colorimetric signal, with its surface modification on the hybrid nanozyme. With the existence of exosomes, CD63 aptamer recognized and adsorbed them on the surface of the nanozyme, which rescued the enhanced peroxidase activity of the aptamer-modified nanozyme, resulting in a deep-to-moderate color change in the TMB-H2O2 system where the change is visible and can be monitored with ultraviolet-visible spectroscopy. In the context of optimal circumstances, the linear range of this exosome detection method is measured to be 1.6 × 104 to 1.6 × 106 particles/µL with a limit of detection as 3.37 × 103 particles/µL. Generally, a simple and accessible approach to exosome detection is constructed, and a nanozyme-based colorimetric aptamer sensor is proposed, which sheds light on novel oncological biomarker measurements in the field of biosensors.

Single-incision robotic assisted surgery: a nonrandomized cohort pilot study on a novel surgical platform in colorectal surgery.

BACKGROUND: The technological barriers and steep learning curve of single-incision laparoscopic surgery had kept it from further applications. A literature review had reported that robotic technology could preserve its advantages while simplifying its difficulties. This nonrandomized cohort pilot study aims to evaluate the feasibility and safety of single-incision robotic assisted colorectal surgery based on a novel robotic surgical platform, the SHURUI Endoscopic Surgical Robotic System (SR-ENS-600). METHOD: This study enrolled 7 patients with colorectal malignancy who underwent single-incision robotic assisted surgery (SIRAS) at a tertiary general surgery center, and retrospectively included 23 patients who underwent robotic assisted surgery from September 2015 to June 2016 and 35 patients who underwent single-incision laparoscopic surgery from June 2017 to March 2018, which were labeled as the initial in-learning-curve attempts from the same surgical team. The technological feasibility and safety of SIRAS were evaluated. Perioperative outcomes, short-term postoperative outcomes, clinicopathologic outcomes, and follow-up were reported. RESULTS: Six SIRAS operations were completed successfully without eventful intraoperative complications, except for one operation that encountered a large-volume of intraoperative hemorrhage. Two SIRAS cases were converted to multiport laparoscopic surgery because of intraoperative hemorrhage and difficulty in retraction. Postoperative pathology reported satisfactory specimen qualities. There were no short-term postoperative complications, no short-term mortality, no tumor recurrence, or metastasis reported. There was one incisional hernia reported half a year after operation. Patients with advanced staging were sent to standard evaluation and chemotherapy, and follow-up is still on-going. CONCLUSIONS: SIRAS can be feasibly performed by a skilled surgical team via the SR-ENS-600 platform for strictly-selected patients, which provides preferable instrument maneuverability and stability in confined surgical fields and overcomes the technical difficulty of multisite dissection through a single-incision. Large-volume investigations and high-level evidences are required to further validate its safety and superiority.

Excessive HSP70/TLR2 activation leads to remodeling of the tumor immune microenvironment to resist chemotherapy sensitivity of mFOLFOX in colorectal cancer.

For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC.

Colorectal cancer vaccines: The current scenario and future prospects.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.

Clinical Status and Future Prospects of Transanal Total Mesorectal Excision.

Low rectal cancer has always posed surgical challenges to gastrointestinal surgeons. Transanal total mesorectal excision (taTME) is a novel approach to radical resection for low rectal cancer. Compared with conventional laparoscopic TME (laTME), taTME is relevant to the benefits of better vision of the mesorectal plane, feasibility of operating in a narrow pelvis, and exact definition of distal resection margin, which may lead to a higher possibility of free circumferential resection margin, better quality of TME specimen, and lower conversion rate. Although there are concerns about its long-term oncological outcomes and complex learning curve, taTME is a promising alternative for rectal cancer. In this review, we discuss the application status and prospects of taTME.

Publisher Correction: A Fast and Refined Cancer Regions Segmentation Framework in Whole-slide Breast Pathological Images.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Fast and Refined Cancer Regions Segmentation Framework in Whole-slide Breast Pathological Images.

Supervised learning methods are commonly applied in medical image analysis. However, the success of these approaches is highly dependent on the availability of large manually detailed annotated dataset. Thus an automatic refined segmentation of whole-slide image (WSI) is significant to alleviate the annotation workload of pathologists. But most of the current ways can only output a rough prediction of lesion areas and consume much time in each slide. In this paper, we propose a fast and refined cancer regions segmentation framework v3_DCNN, which first preselects tumor regions using a classification model Inception-v3 and then employs a semantic segmentation model DCNN for refined segmentation. Our framework can generate a dense likelihood heatmap with the 1/8 side of original WSI in 11.5 minutes on the Camelyon16 dataset, which saves more than one hour for each WSI compared with the initial DCNN model. Experimental results show that our approach achieves a higher FROC score 83.5% with the champion's method of Camelyon16 challenge 80.7%. Based on v3 DCNN model, we further automatically produce heatmap of WSI and extract polygons of lesion regions for doctors, which is very helpful for their pathological diagnosis, detailed annotation and thus contributes to developing a more powerful deep learning model.