Tumor Infiltration Research Articles

A machine learning model reveals expansive downregulation of ligand-receptor interactions that enhance lymphocyte infiltration in melanoma with developed resistance to immune checkpoint blockade

Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance frequently develops. To explore ICB resistance mechanisms, we develop Immunotherapy Resistance cell-cell Interaction Scanner (IRIS), a machine learning model aimed at identifying cell-type-specific tumor microenvironment ligand-receptor interactions relevant to ICB resistance. Applying IRIS to deconvolved transcriptomics data of the five largest melanoma ICB cohorts, we identify specific downregulated interactions, termed resistance downregulated interactions (RDI), as tumors develop resistance. These RDIs often involve chemokine signaling and offer a stronger predictive signal for ICB response compared to upregulated interactions or the state-of-the-art published transcriptomics biomarkers. Validation across multiple independent melanoma patient cohorts and modalities confirms that RDI activity is associated with CD8 + T cell infiltration and highly manifested in hot/brisk tumors. This study presents a strongly predictive ICB response biomarker, highlighting the key role of downregulating chemotaxis-associated ligand-receptor interactions in inhibiting lymphocyte infiltration in resistant tumors.

Light-Controlled Bioorthogonal Chemistry Altered Natural Killer Cell Activity for Boosted Adoptive Immunotherapy.

Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, its practical application is still suffering from the decreased function and inadequate infiltration of NK cells in the immunosuppressive microenvironment of solid tumors. Herein, we construct light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on the NK cell surface, a catalytic array with light-harvesting capabilities is formed. This functionality transforms NK cells into cellular factories capable of catalyzing the production of active agents in a light-controlled manner. NK@p-Fe can generate the active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, NK@p-Fe can also bioorthogonally catalyze the production of the FDA-approved immune agonist imiquimod (IMQ). The activated immune agonist plays a dual role, inducing dendritic cell maturation for NK cell activation and reshaping the tumor immunosuppressive microenvironment for NK cell infiltration. This work represents a paradigm for the modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.

Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies.

Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.

IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion.

The CD8+ T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N6-methyladenosine (m6A) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8+ T cells' antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8+ T cells' antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the m6A site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8+ T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8+ T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.

Construction and validation of a prognostic model of angiogenesis-related genes in multiple myeloma

BackgroundAngiogenesis is associated with tumour growth, infiltration, and metastasis. This study aimed to detect the mechanisms of angiogenesis-related genes (ARGs) in multiple myeloma (MM) and to construct a new prognostic model.MethodsMM research foundation (MMRF)-CoMMpass cohort, GSE47552, GSE57317, and ARGs were sourced from public databases. Differentially expressed genes (DEGs) in the tumour and control cohorts in GSE47552 were determined through differential expression analysis and were enriched with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Weighted gene coexpression network analysis (WGCNA) was applied to derive modules linked to the ARG scores and obtain module genes in GSE47552. Differentially expressed ARGs (DE-ARGs) were selected for subsequent analyses by overlapping DEGs and module genes. Furthermore, prognostic genes were selected using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Depending on the prognostic genes, a risk model was constructed, and risk scores were determined. Moreover, MM samples from MMRF-CoMMpass were sorted into high- and low-risk teams on account of the median risk score. Additionally, correlations among clinical characteristics, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), immune analysis, immunotherapy predictions and the mRNA‒miRNA‒lncRNA network were carried out.ResultsA total of 898 DEGs, 211 module genes, 24 DE-ARGs and three prognostic genes (AKAP12, C11orf80 and EMP1) were selected for this study. Enrichment analysis revealed that the DEGs were related to 86 GO terms, such as ‘cytoplasmic translation’, and 41 KEGG pathways, such as ‘small cell lung cancer’. A prognostic gene-based risk model was created in MMRF-CoMMpass and confirmed with the GSE57317 dataset. Moreover, a nomogram was established on the basis of independent prognostic factors that have proven to be good predictors. In addition, the immune cell infiltration results suggested that memory B cells were enriched in the high-risk group and that immature B cells were enriched in the low-risk group. Finally, the mRNA‒miRNA‒lncRNA network demonstrated that hsa-miR-508-5p was tightly associated with EMP1 and AKAP12. RT‒qPCR was used to validate the expression of the genes associated with prognosis.ConclusionA new prognostic model of MM associated with ARGs was created and validated, providing a new perspective for exploring the connection between ARGs and MM.

The peritumoral brain zone in glioblastoma: a review of the pretreatment approach.

Glioblastomas are the most common and aggressive form of malignant primary brain tumors in adults. The standard treatment is surgical resection followed by radiotherapy and chemotherapy. Despite optimal treatment methods, the prognosis for patients remains poor. Preoperative determination of glioblastoma margins remains beneficial for the complete removal of the tumor mass. Radiotherapy is essential for post-surgery treatment, but radioresistance is a significant challenge contributing to high mortality rates. Advanced imaging technologies are used to analyze the changes in the peritumoral brain zone (PTZ). Consequently, they may lead to the development of novel therapeutic options, especially targeting the marginal parts of a tumor, which could improve the prognosis of glioblastoma patients. The clinical presentation of glioblastoma is heterogeneous and mostly depends on the location and size of a tumor. Glioblastomas are characterized by both intratumoral cellular heterogeneity and an extensive, diffuse infiltration into the normal tissue bordering a tumor called the PTZ. Neuroimaging techniques, such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), proton magnetic resonance spectroscopy (1H MRS), and chemical exchange saturation transfer (CEST) are useful methods in the evaluation of the tumor infiltration and thus the resection margin.

Phase 2 study of the antitumour activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in patients with recurrent and/or metastatic cervical squamous cell carcinoma

Simlukafusp alfa (FAP-IL2v) is an immune cytokine engineered to selectively promote immune responses in the tumour microenvironment. We evaluated the antitumour activity and safety of FAP-IL2v plus atezolizumab in recurrent and/or metastatic cervical squamous cell carcinoma (SCC) in a phase 2 basket study (NCT03386721). Patients with confirmed metastatic, persistent or recurrent cervical SCC who had progressed on ≥1 anti-cancer therapy and had measurable disease were enrolled. FAP-IL2v 10mg was administered once every 3 weeks (Q3W) or once weekly (QW) for 4 weeks then once every 2 weeks (Q2W) with the corresponding Q3W or Q2W atezolizumab regimens. The primary endpoint was objective response rate by investigator assessment. Forty-eight patients were enrolled (Q3W: n=47; QW/Q2W: n=1). Among 45 response evaluable patients, objective responses occurred in 12 patients (27%; CI 16.0-41.0), including 3 complete and 9 partial responses. Responses occurred in 6/19 PD-L1 positive patients (32%; 95% CI 15.4-54.0) and 5/24 PD-L1 negative patients (21%; 95% CI 9.2-35.6). Median duration of response was 13.3 months (95% CI 7.6-NE). Median progression-free survival was 3.7 months (95% CI 3.3-9.0). Adverse events (AEs) were consistent with the known safety profile of each drug. AEs leading to withdrawal of either agent occurred in 6 patients (13%). Pronounced expansion and activation of natural killer and CD8 T cells in peripheral blood and increased tumour infiltration and inflammation were observed. FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC. F. Hoffmann-La Roche Ltd.

Cell cycle inhibitors activate hypoxia-induced DDX41-STING pathway to mediate anti-tumor immune response in liver cancer.

Cell cycle inhibitors have a long history as cancer treatment. Here, we reported that these inhibitors combated cancer partially via Stimulator of IFN genes (STING) signaling pathway. We demonstrated that Paclitaxel (microtubule stabilizer), Palbociclib (cyclin dependent kinase 4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anti-cancer functions beyond arresting cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic HCC cells more sensitive to the anti-mitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment of cell cycle inhibitors, especially Paclitaxel, extends survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that Paclitaxel suppressed STINGWT HCC more effectively than STINGKO HCC, suggesting that STING might contribute to the anti-tumor effects of Paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

Advanced imaging reveals enhanced malignancy in glioblastomas involving the subventricular zone: evidence of increased infiltrative growth and perfusion.

Glioblastoma's infiltrative growth and heterogeneity are influenced by neural, molecular, genetic, and immunological factors, with the precise origin of these tumors remaining elusive. Neurogenic zones might serve as the tumor stem cells' nest, with tumors in contact with these zones exhibiting worse outcomes and more aggressive growth patterns. This study aimed to determine if these characteristics are reflected in advanced imaging, specifically diffusion and perfusion data. In this monocentric retrospective study, 137 glioblastoma therapy-naive patients (IDH-wildtype, grade 4) with advanced preoperative MRI, including perfusion and diffusion imaging, were analyzed. Tumors and neurogenic zones were automatically segmented. Advanced imaging metrics, including cerebral blood volume (CBV) from perfusion imaging, tissue volume mask (TVM), and free water corrected fractional anisotropy (FA-FWE) from diffusion imaging, were extracted. SVZ infiltration positively correlated with CBV, indicating higher perfusion in tumors. Significant CBV differences were noted between high and low SVZ infiltration cases at specific percentiles. Negative correlation was observed with TVM and positive correlation with FA-FWE, suggesting more infiltrative tumor growth. Significant differences in TVM and FA-FWE values were found between high and low SVZ infiltration cases. Glioblastomas with SVZ infiltration exhibit distinct imaging characteristics, including higher perfusion and lower cell density per voxel, indicating a more infiltrative growth and higher vascularization. Stem cell-like characteristics in SVZ-infiltrating cells could explain the increased infiltration and aggressive behavior. Understanding these imaging and biological correlations could enhance the understanding of glioblastoma evolution.

Combination of lipopolysaccharide and polygalacturonic acid exerts antitumor activity and augments anti-PD-L1 immunotherapy

Polygalacturonic acid (PGA) restored the alpha-diversity of gut microbiota and promoted T cells infiltration in tumors. Here, we investigated whether oral administration of PGA could improve the anti-cancer effect of lipopolysaccharide-encapsulated PLGA-PEG-PLGA (LPS/PPP) in mice bearing CT26 tumors. Hydrogels with rapid thermogelling properties can achieve localized and controlled release of LPS, thus retaining the anti-cancer effect of LPS and avoiding a robust inflammatory storm. LPS/PPP promoted M1 macrophage polarization, TLR4 expression, and phagocytosis in tumors. The combination of PGA and LPS/PPP (PGA_LPS) notably repressed CT26 tumor growth and the inhibition rate reached 67.6 %. PGA_LPS triggered the recruitment of helper and cytotoxic T cells, IFN-γ level, decreased the proportion of immunosuppressive regulatory T cells. PGA_LPS also restored the beta-diversity of gut microbiota and increased short chain fatty acids abundance (butyric acid, 608.93 % vs. model group, P < 0.01). PGA_LPS followed by αPD-L1 resulted in obvious inhibition of both CT26 and 4T1 tumor growth, promoted cleaved-caspase 3 and Bax expression, T cell responses and the rescue of T cells exhaustion. These results confirmed that PGA_LPS reinforced the anticancer effect of αPD-L1, probably by reshaping the tumor microenvironment and intestinal flora, which sheds light on the combination approach to intensify the effect of immune checkpoint inhibitors.

Riluzole Enhancing anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.

Colorectal cancer is the second leading cause of cancer mortality in the US. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of colorectal cancer patients, response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cGAS/STING pathway in colon cancer cells, resulting in increased expression of interferon β (IFNβ) and IFNβ-regulated genes including CXCL10. Inhibition of ATM, but not ATR, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contribute to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent, and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies. .

A case report: mucinous carcinoma of extrahepatic bile ducts with periportal calcification suggestive of lymphatic calcification.

Mucinous carcinoma is a rare subtype of extrahepatic bile duct (EHBD) cancer in which abundant mucin surrounds cancer cell nests. Calcification is often observed in mucus-producing tumors, and we herein report a case of mucinous carcinoma of EHBD with diffuse periportal calcifications. A 92-year-old woman was seen for jaundice. Non-contrast CT showed diffuse semi-linear branching calcifications extending from the hepatoduodenal ligament along the long axis of the intra- and extrahepatic portal veins. A bile duct mass and multiple lymph nodes were hyperintense on T2-weighted MRI images, and periportal abnormal intensity was visible along the intrahepatic portal tract. On contrast-enhanced CT, the mass and enlarged lymph nodes showed a weak enhancing effect. In addition, a lesion with a similar enhancing effect was observed in parallel with periportal calcification, raising suspicion of tumor extension. An endoscopic bile duct biopsy was performed, which resulted in the tumor being diagnosed as a mucinous carcinoma. Considering the imaging findings, it was determined to be a mucinous carcinoma of EHBD origin, with lymphatic vessel infiltration and multiple lymph node metastases. The lymphatic tracts presented lymphangitic carcinomatosis extending from the hepatoduodenal ligament to intrahepatic portal tracts, and the diffuse periportal calcification was presumed to be calcification associated with the mucin component of tumor infiltration.

Modified Hemocyanins from Rapana thomasiana and Helix aspersa Exhibit Strong Antitumor Activity in the B16F10 Mouse Melanoma Model.

Melanoma is one of the most common tumors worldwide, and new approaches and antitumor drugs for therapy are being investigated. Among the promising biomolecules of natural origin for antitumor research are gastropodan hemocyanins-highly immunogenic multimeric glycoproteins used as antitumor agents and components of therapeutic vaccines in human and mouse cancer models. A murine melanoma model established in C57BL/6 mice of the B16F10 cell line was used to study anticancer modified oxidized hemocyanins (Ox-Hcs) that were administered to experimental animals (100 μg/mouse) under different regimens: mild, intensive, and with sensitization. The solid tumor growth, antitumor response, cell infiltration in tumors, and survival were assessed using flow cytometry, ELISA, and cytotoxicity assays. Therapy with Ox-RtH or Ox-HaH resulted in the generation of enhanced specific immune response (increased levels of tumor-infiltrated mature NK cells (CD27+CD11b+) in sensitized groups and of macrophages in the intensively immunized animals) and tumor suppression. Beneficial effects such as delayed tumor incidence and growth as well as prolonged survival of tumor-bearing animals have been observed. High levels of melanoma-specific CTLs that mediate cytotoxic effects on tumor cells; tumor-infiltrating IgM antibodies expected to enhance antibody-dependent cellular cytotoxicity; type M1 macrophages, which stimulate the Th1 response and cytotoxic cells; and proinflammatory cytokines, were also observed after Ox-Hcs administration. The modified Hcs showed strong antitumor properties in different administration regimens in a murine model of melanoma with potential for future application in humans.

Prospective observational non-randomized trial protocol for surgical planner 3D image processing & reconstruction for locally advanced colon cancer

IntroductionColon cancer presents significant surgical challenges that necessitate the development of precise strategies. Standardization with complete mesocolic excision (CME) is common, but some cases require extended resections. This study investigates the use of 3D Image Processing and Reconstruction (3D-IPR) to improve diagnostic accuracy in locally advanced colon cancer (LACC) with suspected infiltration and achieve R0 surgery.MethodsSingle-center, prospective, observational, comparative, non-randomized study.•Participants: Patients aged > 18 years undergoing LACC surgery, as indicated by CT scans, confirmed via colonoscopy. Exclusion criteria include neoadjuvant therapy, suspected carcinomatosis on CT, and unresectable tumors.•Interventions: 3D-IPR models are used for surgical planning, providing detailed tumor and surrounding structure metrics. Surgical procedures are guided by CT scans and intraoperative findings, categorized by surgical margins as R0, R1, or R2.•Objective: The primary goal is to evaluate 3D-IPR’s utility in achieving R0 resection in LACC with suspected infiltration. Secondary objectives include assessing preoperative surgical strategy, comparing CT reports, detecting adenopathy, and identifying vascularization and anatomical variants.• Outcome: The main outcome is the diagnostic accuracy of 3D-IPR in determining tumor infiltration of neighboring structures compared to conventional CT scans, using definitive pathological reports as the gold standard.Results•Recruitment and Number Analyzed: The study aims to recruit about 20 patients annually over two years, focusing on preoperative 3D-IPR analysis and subsequent surgical procedures.•Outcome Parameters: These include loco-regional and distant recurrence rates, peritoneal carcinomatosis, disease-free and overall survival, and mortality due to oncologic progression.•Harms: No additional risks from CT scans, as they are mandatory for staging colon tumors. 3D-IPR is derived from these CT scans.DiscussionIf successful, this study could provide an objective tool for precise tumor extension delimitation, aiding decision-making for radiologists, surgeons, and multidisciplinary teams. Enhanced staging through 3D-IPR may influence therapeutic strategies, reduce postsurgical complications, and improve the quality of life of patients with LACC.Trial registrationTrial is registered at ISRCTN registry as ISRCTN81005215. Protocol version I (Date 29/06/2023).

A locally infiltrative juxtaglomerular cell tumor with unusual histologic features.

A locally infiltrative juxtaglomerular cell tumor with unusual histologic features.

Dual-responsive natural killer cell nano-engagers for cancer immunotherapy via inhibiting IL-6/JAK2/STAT3 pathway

Natural killer (NK) cell-based immunotherapy is a promising approach for treating solid tumors and hematological malignancies. However, its therapeutic efficacy is limited by poor tumor infiltration and suppressive tumor microenvironment. Here, we introduce a rapid, simple, and efficient solution: bovine serum albumin-stabilized ultra-small (4 nm) NK cell nano-engagers, termed Bi2Se3@BSA nanodots (Nds). These Nds, responsive to high H2O2 levels in tumor cell environments, enhance near-infrared (NIR)-II photothermic immunotherapy. In vitro and in vivo experiments demonstrate their effectiveness in activating photothermal therapy (PTT)-induced immunogenic cell death (ICD), initiating immune cascade reactions, and stimulating immune response activation. By upregulating NKG2D, RAE-1, and secreting cytokines such as IFN-γ and TNF-α, targeted NK cell infiltration is achieved, reversing the immunosuppressive tumor microenvironment and optimizing NK cell cytotoxicity. Transcriptomic analysis confirms the association of immune response activation with the IL-6/JAK2/STAT3 signaling pathway. Notably, combining these nano-engagers with immune checkpoint inhibitors (aPD-1) significantly enhances therapeutic efficacy, facilitating tumor eradication and reducing recurrence risk. Taken together, NK cell nano-engagers inhibit the IL-6/JAK2/STAT3 signaling pathway, target NK cell activation, stimulate immune functions, and improve the immunosuppressive microenvironment. This study presents an alternative strategy for NK cell-based immunotherapy and highlights this promising tool for cancer immunotherapy.

Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma

BackgroundCertain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these,...

Expression, Characteristics, and Clinical Target Prediction of PIK3C3/ vps34 in Gastric Cancer.

This study aimed to investigate the expression pattern of phosphatidylinositol 3-kinase class III (PIK3C3/vps34) in gastric cancer (GC) tissues and their juxtaposed normal counterparts and its correlation with the clinicopathological attributes and prognostic outlook of afflicted individuals. Immunohistochemical (IHC) staining was used to ascertain the expression levels of PIK3C3/vps34 across 60 GC tissues juxtaposed with their normal counterparts. Statistical methodologies were used to scrutinize the correlation between PIK3C3/vps34 expression and clinicopathological features, along with prognostic implications for GC patients. In GC tissues, the positive expression rate of PIK3C3/vps34 was 23.3% (14/60), which contrasted sharply with the markedly elevated rate of 66.7% (40/60) observed in adjacent tissues. The positive expression proportion of PIK3C3/vps34 within GC tissues exhibited a notable decrease than in adjacent tissues (P<0.05). The expression of PIK3C3/vps34 inverse-ly correlated with tumor size, degree of tissue differentiation, depth of tumor infiltration, and incidence of lymph node metastasis (P<0.05), whereas no significant associations were found with patient sex, age, tumor location, TNM staging, or distant metastasis (P > 0.05). As the tumor diameter increases, the degree of tissue differentiation diminishes, tumor infiltration depth intensifies, lymph node metastasis emerges, the TNM stage progresses, and PIK3C3/vps34 expression level within GC tissues declines correspondingly. Kaplan-Meier survival analysis unveiled a prolonged survival duration among GC patients exhibiting heightened PIK3C3/vps34 expression than in their counterparts with diminished expression (HR=0.66, 95% CI: 0.55-0.80), demonstrating statistical significance (P<0.05). Protein interaction analysis revealed noteworthy interactions involving PIK3C3 with Beclin 1, UVRAG, and ATG14. PIK3C3/vps34 is downregulated in GC tissues, exerting a pivotal role in tumorigenesis, and is intimately linked with the prognostic trajectory of GC patients. It may serve as a significant biomarker for prognostic evaluation and a promising molecular therapeutic target for GC.

Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.

The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.

Optimal Setup and Parameters of Diffusion-Weighted Magnetic Resonance Imaging for Translational Evaluation of a Tumor Progression Model for Soft Tissue Sarcomas

PurposeDefining a microscopic tumor infiltration boundary is critical to the success of radiation therapy. Currently, radiation oncologists use margins to geometrically expand the visible tumor for radiation treatment planning in soft tissue sarcomas (STS). Image-based models of tumor progression would be critical to personalize treatment radiation field to the pattern of sarcoma spread. Evaluation of these models is necessary to demonstrate feasibility in the clinical setting. This study presents an imaging protocol for the preclinical evaluation of a tumor progression model in extremity STS. MethodsWe recruited seven healthy volunteers and acquired diffusion-weighted MRI (DW-MRI) images of the thigh on an MRI scanner used for imaging cancer patients in a radiation oncology department. We developed a protocol, which includes positioning the patient, configuring the RF coils, and setting the diffusion-weighted MRI sequence parameters. To find the optimal parameter configuration, the image signal-to-noise ratio (SNR) and the directional variability (DV) of the principal eigenvector of the diffusion tensor were calculated. ResultsThe mean SNR across all trials and 12 thigh muscles was 41 with a range of 12 to 72. The mean DV was 13° and ranged from 11° to 23°. The longest scan time was 22 min 58 s and the shortest 11 min 46 s. For the high-resolution image with a voxel volume of 1.3×1.3×6 mm3 and 38 slices, the optimal parameters were found to be a repetition time of 8000 ms, 12 signal averages, and 6 gradient directions. This configuration resulted in a scan time of 11 min 46 s, an SNR of 34, and a DV of 13°. ConclusionsA DW-MRI scan duration acceptable for imaging cancer patients was achieved with an image quality suitable for reproducible modeling of tumor infiltration. The developed protocol can be used for preclinical evaluation in STS patients.