ACIR Journal Articles

Extracellular Vesicles Released by Glioblastoma Cancer Cells Drive Tumor Invasiveness via Connexin-43 Gap Junctions

(1) Tamborini M (2) Ribecco V (3) Stanzani E (4) Sironi A (5) Tambalo M (6) Franzone D (7) Florio E (8) Fraviga E (9) Saulle C (10) Gagliani MC (11) Pizzocri M (12) Mattioli M (13) Cortese K (14) Jiang JX (15) Martano G (16) Politi LS (17) Riva M (18) Pessina F (19) Pozzi D (20) Lodato S (21) Passoni L (22) Matteoli M

Neuro-oncology

BACKGROUND: Although invasiveness is one of the major determinants of the poor glioblastoma (GBM) outcome, the mechanisms of GBM invasion are only partially understood. Among the intrinsic and environmental processes promoting cell-to-cell interaction processes, eventually driving GBM invasion, we focused on the pro-invasive role played by Extracellular Vesicles (EVs), a heterogeneous group of cell-released membranous structures containing various bioactive cargoes, which can be transferred from donor to recipient cells. METHODS: EVs isolated from patient-derived GBM cell lines and surgical aspirates were assessed for their pro-migratory competence by spheroid migration assays, calcium imaging, and PYK-2/FAK phosphorylation. Brain invasiveness was investigated in human cortical organoids-based assembloids and in vivo orthotopic xenografts. EV molecular features were specified by multiplex bead-based flow cytometry. RESULTS: Results unveil a self-sustaining mechanism triggering migration through autocrine release and engagement of a specific population of EVs of large size (L-EVs), isolated from either patient-derived cell lines or surgical aspirates. L-EVs act through modulation of calcium transients via Connexin 43-Gap Junctions (Cx43-GJ) and phospho-activation of PYK2. Pre-incubation with blocking antibodies targeting Cx43 hemichannels demonstrated a dose-dependent inhibition of the L-EV-mediated GBM migration. By exploiting patients' surgical aspirates, we show that only L-EVs deriving from tumoral cells, and not those with immune origin, promote tumor migration, impacting more prominently the tumoral cells with mesenchymal subtype. CONCLUSIONS: We demonstrate that L-EVs released by GBM cells, but not by the immune cells of the tumor microenvironment, represent a relevant and unique autocrine pro-migratory input for the tumor.

Author Info: (1) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (2) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (3) IRCCS Humanitas Research Hospital; R

Author Info: (1) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (2) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (3) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. CNR Institute of Neuroscience c/o Humanitas Research Hospital, Rozzano, Italy. (4) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (5) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (6) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (7) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (8) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (9) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (10) Department of Experimental Medicine (DIMES), Cellular Electron Microscopy Laboratory, Universit di Genova; Genova 16132, Italy. (11) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (12) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (13) Department of Experimental Medicine (DIMES), Cellular Electron Microscopy Laboratory, Universit di Genova; Genova 16132, Italy. (14) Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio; San Antonio, TX. (15) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (16) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (17) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (18) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (19) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (20) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy. (21) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. (22) IRCCS Humanitas Research Hospital; Rozzano (Milano) 20089, Italy. Humanitas University, Department of Biomedical Sciences; Pieve Emanuele (Milano) 20072, Italy.

Citation: Neuro Oncol 2025 Jan 30 Epub01/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39883079

Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma

(1) Grimes JM (2) Ghosh S (3) Manzoor S (4) Li LX (5) Moran MM (6) Clements JC (7) Alexander SD (8) Markert JM (9) Leavenworth JW

Nature communications - Open Access

(1) Grimes JM (2) Ghosh S (3) Manzoor S (4) Li LX (5) Moran MM (6) Clements JC (7) Alexander SD (8) Markert JM (9) Leavenworth JW

Nature communications - Open Access

Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4(+) T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4(+) T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4(+) T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4(+) T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4(+) T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy.

Author Info: (1) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL,

Author Info: (1) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA. (2) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (3) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (4) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (5) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA. (6) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (7) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (8) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. (9) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu. The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu.

Citation: Nat Commun 2025 Jan 30 16:1095 Epub01/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39885128

Cross-priming in cancer immunology and immunotherapy

(1) Luri-Rey C (2) Teijeira ç (3) Wculek SK (4) de Andrea C (5) Herrero C (6) Lopez-Janeiro A (7) Rodrguez-Ruiz ME (8) Heras I (9) Aggelakopoulou M (10) Berraondo P (11) Sancho D (12) Melero I

Nature reviews. Cancer

(1) Luri-Rey C (2) Teijeira ç (3) Wculek SK (4) de Andrea C (5) Herrero C (6) Lopez-Janeiro A (7) Rodrguez-Ruiz ME (8) Heras I (9) Aggelakopoulou M (10) Berraondo P (11) Sancho D (12) Melero I

Nature reviews. Cancer

Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40-CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8(+) T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8(+) T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far.

Author Info: (1) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. (2) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain

Author Info: (1) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. (2) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (3) Innate Immune Biology Laboratory, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. (4) Department of Pathology, Clnica Universidad de Navarra, Pamplona, Spain. (5) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Department of Pathology, Clnica Universidad de Navarra, Pamplona, Spain. (6) Department of Pathology, Clnica Universidad de Navarra, Pamplona, Spain. (7) Department of Radiation Oncology, Clnica Universidad de Navarra, Pamplona, Spain. (8) Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (9) Nuffield Department of Medicine, University of Oxford, Oxford, UK. (10) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (11) Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (12) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. imelero@unav.es. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. imelero@unav.es. Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. imelero@unav.es. Nuffield Department of Medicine, University of Oxford, Oxford, UK. imelero@unav.es. Departments of Immunology and Oncology, Clnica Universidad de Navarra, Pamplona, Spain. imelero@unav.es.

Citation: Nat Rev Cancer 2025 Jan 29 Epub01/29/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39881005

Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics

(1) Chekalin E (2) Paithankar S (3) Shankar R (4) Xing J (5) Xu W (6) Chen B

Bioinformatics advances - Open Access | Free PMC Article

(1) Chekalin E (2) Paithankar S (3) Shankar R (4) Xing J (5) Xu W (6) Chen B

Bioinformatics advances - Open Access | Free PMC Article

MOTIVATION: Bispecific antibodies (bsAbs) that bind to two distinct surface antigens on cancer cells are emerging as an appealing therapeutic strategy in cancer immunotherapy. However, considering the vast number of surface proteins, experimental identification of potential antigen pairs that are selectively expressed in cancer cells and not in normal cells is both costly and time-consuming. Recent studies have utilized large bulk RNA-seq databases to propose bispecific targets for various cancers. However, co-expressed pairs derived from bulk RNA-seq do not necessarily indicate true co-expression of both markers in malignant cells. Single-cell RNA-seq (scRNA-seq) can circumvent this issue but the issues in low coverage of transcripts impede the large-scale characterization of co-expressed pairs. RESULTS: We present a computational pipeline for bsAbs target identification which combines the advantages of bulk and scRNA-seq while minimizing the issues associated with using these approaches separately. We select hepatocellular carcinoma (HCC) as a case study to demonstrate the utility of the approach. First, using the bulk RNA-seq samples in the OCTAD database, we identified target pairs that most distinctly differentiate tumor cases from healthy controls. Next, we confirmed our findings on the scRNA-seq database comprising 39 361 healthy cells from vital organs and 18 000 cells from HCC tumors. The top pair was GPC3-MUC13, where both genes are co-expressed on the surface of over 30% of malignant hepatocytes and have very low expression in other cells. Finally, we leveraged the emerging spatial transcriptomic to validate the co-expressed pair in situ. AVAILABILITY AND IMPLEMENTATION: A standalone R package (https://github.com/Bin-Chen-Lab/bsAbsFinder).

Author Info: (1) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. (2) Department of Pediatrics and Human Development, Michigan S

Author Info: (1) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. (2) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. (3) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. (4) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. (5) Hengenix Biotech, Inc., Milpitas, CA 95035, United States. (6) Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, United States. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States. Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, United States.

Citation: Bioinform Adv 2024 4:vbae096 Epub06/20/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39872360

Ultrasound-Enhanced Spleen-Targeted mRNA Delivery via Fluorinated PEGylated Lipid Nanoparticles for Immunotherapy

(1) Chen M (2) Cen J (3) Shi Q (4) Shao B (5) Tan J (6) Ye X (7) He Z (8) Liu Y (9) Zhang G (10) Hu J (11) Bao J (12) Liu S

Angewandte Chemie

(1) Chen M (2) Cen J (3) Shi Q (4) Shao B (5) Tan J (6) Ye X (7) He Z (8) Liu Y (9) Zhang G (10) Hu J (11) Bao J (12) Liu S

Angewandte Chemie

Lipid nanoparticles (LNPs) based messenger RNA (mRNA) therapeutics hold immense promise for treating a wide array of diseases, while their nonhepatic organs targeting and insufficient endosomal escape efficiency remain challenges. For LNPs, polyethylene glycol (PEG) lipids have a crucial role in stabilizing them in aqueous medium, but they severely hinder cellular uptake and reduce transfection efficiency. In this study, we designed ultrasound (US)-assisted fluorinated PEGylated LNPs (F-LNPs) to enhance spleen-targeted mRNA delivery and transfection. Through liquid-to-gas phase transition, we enabled the controlled shedding of fluorinated PEG lipids from F-LNPs, facilitating cellular uptake, membrane fusion, and mRNA release. In vivo results demonstrated that US-assisted F-LNPs increased mRNA transfection approximately 4.0-fold in the spleen following intravenous administration. Notably, the F-LNPs achieved effective mRNA delivery to antigen-presenting cell subsets, such as dendritic cells, macrophages, and B cells. The targeted delivery of full-length ovalbumin-encoding mRNA vaccine induced significant CD8+ T cell response and exhibited excellent therapeutic effect against the ovalbumin-transduced B16F10 tumor model. These findings establish a novel strategy for spleen-specific mRNA delivery through the combination of fluorinated PEG lipids and US treatment, which holds substantial promise for enhancing the efficacy of immunotherapy, potentially broadening the scope of clinical applications for mRNA-based therapy.

Author Info: (1) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (2) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (3)

Author Info: (1) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (2) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (3) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (4) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (5) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (6) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (7) USTC: University of Science and Technology of China, Department of Pediatrics, CHINA. (8) USTC: University of Science and Technology of China, Department of Pediatrics, CHINA. (9) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (10) USTC: University of Science and Technology of China, Department of Pharmacy, 96 Jinzhai Road, Department of Polymer Science and Engineering, University of Sc, Hefei, 230026, Hefei, CHINA. (11) USTC: University of Science and Technology of China, Department of Pharmacy, CHINA. (12) University of Science and Technology of China School of Biomedical Engineering, Department of Polymer Science and Engineering, 96 Jinzhai Road, 230026, Hefei, CHINA.

Citation: Angew Chem Int Ed Engl 2025 Jan 29 e202500878 Epub01/29/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39878170

Infiltration and subtype analysis of CD3 + CD20 + T cells in lung cancer

(1) Luo L (2) Ji J (3) Dong J (4) He M (5) Jiang W (6) Liu Y (7) Wang W

BMC cancer - Open Access

(1) Luo L (2) Ji J (3) Dong J (4) He M (5) Jiang W (6) Liu Y (7) Wang W

BMC cancer - Open Access

Background: CD3 + CD20 + T cells (TB cells) are a subset of lymphocytes in the human body that are associated with inflammation. They originate from T cells interacting with B cells, and their levels are abnormally elevated in individuals with immune disorders, as well as in some cancer patients. The interplay between tumor immunity and inflammation is intricate, yet the specific involvement of TB cells in local tumor immunity remains uncertain, with limited research on their subtypes.

Methods: Lung cancer surgical samples were stained using multi-color immunofluorescence to study the subtypes and distribution patterns of TB cells.

Results: TB cells were confirmed to exist in a scattered pattern within tertiary lymphoid structures (TLS) in lung cancer tissues, with higher abundance in mature TLS. In subtype analysis, the CD4-CD8- double-negative TB cell subtype was predominant, comprising over 90% in samples with abundant TLS infiltration and over 60% in samples with poor infiltration. This was followed by the CD4 + CD8- and CD4-CD8 + single-positive TB cell subtypes, while the CD4 + CD8 + double-positive TB cell subtype was nearly absent. During the maturation of TLS, the proportion of B cells gradually increased, while the proportion of CD4-CD8- T cell subtype decreased.

Conclusions: TB cells extensively infiltrate the TLS regions in tumor tissues, with the double-negative subtype being predominant, potentially playing a crucial regulatory role in the local tumor immune microenvironment. This finding could facilitate the advancement of novel cancer treatment strategies.

Author Info: (1) Basic Research Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Sci

Author Info: (1) Basic Research Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China. (2) Pathology Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China. (3) Department of Pulmonology, Meishan Cancer Hospital, Meishan, China. (4) Pathology Department, Meishan Cancer Hospital, Meishan, China. (5) Basic Research Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China. Radiotherapy Center, Radiation Oncology Key Laboratory of Sichuan Province, Clinical Research Center for Cancer, Sichuan Cancer Center, Chengdu, Sichuan, China. (6) Pathology Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China. liuyanglyon@uestc.edu.cn. (7) Basic Research Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China. wwdwyl@uestc.edu.cn. Radiotherapy Center, Radiation Oncology Key Laboratory of Sichuan Province, Clinical Research Center for Cancer, Sichuan Cancer Center, Chengdu, Sichuan, China. wwdwyl@uestc.edu.cn.

Citation: BMC Cancer 2025 Jan 30 25:179 Epub01/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39885465

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer

(1) Ren Y (2) Xue M (3) Hui X (4) Liu X (5) Farooq MA (6) Chen Y (7) Ji Y (8) Duan Y (9) Ajmal I (10) Yao J (11) Jiang W

Pharmacological research - Open Access

(1) Ren Y (2) Xue M (3) Hui X (4) Liu X (5) Farooq MA (6) Chen Y (7) Ji Y (8) Duan Y (9) Ajmal I (10) Yao J (11) Jiang W

Pharmacological research - Open Access

ABSTRACT: Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body's anti-cancer defense, and chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.

Author Info: (1) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; College of Life Science, Xinjiang Normal Universit

Author Info: (1) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; College of Life Science, Xinjiang Normal University, Urumqi 830054, China. (2) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (3) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (4) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (5) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (6) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (7) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (8) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (9) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (10) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. (11) Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: wzjiang@bio.ecnu.edu.cn.

Citation: Pharmacol Res 2025 Jan 28 107637 Epub01/28/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39884449

Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity Spotlight

(1) Vogt KC (2) Silberman PC (3) Lin Q (4) Han JE (5) Laflin A (6) Gellineau HA (7) Heller DA (8) Scheinberg DA

Science advances - Open Access | Free PMC Article

Vogt and Silberman et al. engineered TME-actuated T cells (MEAT cells) using an αP-selectin synNotch to restrict CAR expression to malignant tissue. MEAT cells demonstrated P-selectin-specific actuation and CAR expression, activation, and target cell killing in vitro. Compared to conventional GD2 CAR T cells, which caused fatal neurotoxicity, P-selectin-gated GD2 CAR T cells in mice bearing neuroblastomas demonstrated antitumor efficacy, without detectable neurotoxicity or T cell infiltration in the brain. P-selectin-gated CD19 CAR T cells showed improved metabolic fitness, higher persistence, and enhanced antitumor efficacy in vivo.

Contributed by Shishir Pant

(1) Vogt KC (2) Silberman PC (3) Lin Q (4) Han JE (5) Laflin A (6) Gellineau HA (7) Heller DA (8) Scheinberg DA

Science advances - Open Access | Free PMC Article

ABSTRACT: A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2(+) normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.

Author Info: (1) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065

Author Info: (1) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA. (3) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. BCMB Program, Weill Cornell Medicine, New York, NY 10065, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA. (8) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA.

Citation: Sci Adv 2025 Jan 24 11:eads3403 Epub01/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39841845

Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice Spotlight

(1) Wang H (2) Wu Z (3) Cui D (4) Bian L (5) Zheng Z (6) Zhu J (7) Geng H (8) Sun Z (9) Pan Y (10) Shi Y (11) Yi Q (12) Song Z (13) Li Y (14) Shen K (15) Li Y (16) Shen W (17) Yan H (18) Hao R (19) Sun M (20) Zhang S (21) Zhang C (22) Jin H (23) Zhai B

Science translational medicine

Anti-EpCAM CAR T cells caused lethal cytotoxicity in mice, but caused on-target, off-tumor lung and liver injury. ICAM-1 and VCAM-1 were elevated in these tissues, and blockade of integrins LFA-1 and VLA-4 alleviated toxicity and off-tumor trafficking. Triple knockdown (TKD) of integrin subunits CD11a/CD49 plus PSGL1 (TKD) in the CAR vector mimicked this effect and preserved efficacy. TKD cells had decreased exhaustion/activation, increased memory/anti-apoptotic gene expression, and were more serially cytotoxic in vitro. In a model with hEpCAM, TKD cells exhibited similar tumor infiltration and efficacy to control cells, along with improved persistence and decreased exhaustion.

Contributed by Morgan Janes

Science translational medicine

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapies have revolutionized the landscape of cancer treatment, in particular in the context of hematologic malignancies. However, for solid tumors that lack tumor-specific antigens, CAR-T cells can infiltrate and attack nonmalignant tissues expressing the CAR target antigen, leading to on-target, off-tumor toxicity. Severe on-target, off-tumor toxicities have been observed in clinical trials of CAR-T therapy for solid tumors, highlighting the need to address this issue. Here, we demonstrated that targeting the cell adhesion and migration molecules lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) and very late activation antigen 4 (VLA-4; CD49d/CD29) with blocking antibodies reduced the on-target, off-tumor toxicity of CAR-T cells in mice. To translate this observation into improved CAR-T cell therapy, we either knocked out both CD11a and CD49d or knocked down CD11a and CD49d along with PSGL1, another cell adhesion molecule, in CAR-T cells. We found that these modified CAR-T cells exhibited reduced on-target, off-tumor toxicity in vivo without affecting CAR-T cell efficacy. Furthermore, we showed that this approach promoted T cell memory formation and decreased tonic signaling. On the basis of these data, we engineered a human version of these low-toxicity CAR-T cells and further validated the feasibility of this approach in vitro and in vivo. Together, these results provide a potential solution to address the clinical challenge of on-target, off-tumor toxicity in CAR-T therapy.

Author Info: (1) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Shanghai Cancer Institute, State Key Laboratory

Author Info: (1) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (2) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (3) Mini-invasive Interventional Therapy Center, Shanghai East Hospital, Tongji University, Shanghai 200025, China. (4) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (5) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (6) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (7) Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (8) Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (9) Department of Liver Surgery and Liver Transplantation, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. (10) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (11) Suzhou Immunofoco Biotechnology Co. Ltd, Suzhou, Jiangsu 215000, China. (12) Mini-invasive Interventional Therapy Center, Shanghai East Hospital, Tongji University, Shanghai 200025, China. (13) Suzhou Immunofoco Biotechnology Co. Ltd, Suzhou, Jiangsu 215000, China. (14) Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200025, China. (15) Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200025, China. (16) Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (17) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (18) Suzhou Immunofoco Biotechnology Co. Ltd, Suzhou, Jiangsu 215000, China. (19) Suzhou Immunofoco Biotechnology Co. Ltd, Suzhou, Jiangsu 215000, China. (20) Suzhou Immunofoco Biotechnology Co. Ltd, Suzhou, Jiangsu 215000, China. (21) Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. (22) Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (23) Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Mini-invasive Interventional Therapy Center, Shanghai East Hospital, Tongji University, Shanghai 200025, China.

Citation: Sci Transl Med 2025 Jan 22 17:eadl6432 Epub01/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39841806

Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models Spotlight

(1) Pierini S (2) Gabbasov R (3) Oliveira-Nunes MC (4) Qureshi R (5) Worth A (6) Huang S (7) Nagar K (8) Griffin C (9) Lian L (10) Yashiro-Ohtani Y (11) Ross K (12) Sloas C (13) Ball M (14) Schott B (15) Sonawane P (16) Cornell L (17) Blumenthal D (18) Chhum S (19) Minutolo N (20) Ciccaglione K (21) Shaw L (22) Zentner I (23) Levitsky H (24) Shestova O (25) Gill S (26) Varghese B (27) Cushing D (28) Ceeraz DeLong S (29) Abramson S (30) Condamine T (31) Klichinsky M

Nature communications - Open Access | Free PMC Article

To improve responses in solid tumors, Pierini et al. evaluated the efficacy of engineered macrophages (CAR-M) +/- anti-PD-1 in clinically relevant, fully immunocompetent, syngeneic mouse models. Both regional (intratumoral) and systemic therapy with anti-HER2 CD3-ζ CAR-M remodeled the TME (increased DCs and myeloid cells), activated TILs (CD4⁺ and CD8⁺ T cells, NK cells), induced antigen spreading, protected against antigen-negative relapses, and depended on endogenous T cells for efficacy. CAR-M therapy with anti-PD-1 significantly reduced tumor burden and prolonged survival in mice with solid tumors with limited sensitivity to anti-PD-1 alone.

Contributed by Katherine Turner

Nature communications - Open Access | Free PMC Article

ABSTRACT: We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.

Author Info: (1) Carisma Therapeutics Inc, Philadelphia, PA, USA. (2) Carisma Therapeutics Inc, Philadelphia, PA, USA. (3) Carisma Therapeutics Inc, Philadelphia, PA, USA. (4) Carisma Therapeut

Author Info: (1) Carisma Therapeutics Inc, Philadelphia, PA, USA. (2) Carisma Therapeutics Inc, Philadelphia, PA, USA. (3) Carisma Therapeutics Inc, Philadelphia, PA, USA. (4) Carisma Therapeutics Inc, Philadelphia, PA, USA. (5) Carisma Therapeutics Inc, Philadelphia, PA, USA. (6) Carisma Therapeutics Inc, Philadelphia, PA, USA. (7) Carisma Therapeutics Inc, Philadelphia, PA, USA. (8) Carisma Therapeutics Inc, Philadelphia, PA, USA. (9) Carisma Therapeutics Inc, Philadelphia, PA, USA. (10) Carisma Therapeutics Inc, Philadelphia, PA, USA. (11) Carisma Therapeutics Inc, Philadelphia, PA, USA. (12) Carisma Therapeutics Inc, Philadelphia, PA, USA. (13) Carisma Therapeutics Inc, Philadelphia, PA, USA. (14) Carisma Therapeutics Inc, Philadelphia, PA, USA. (15) Carisma Therapeutics Inc, Philadelphia, PA, USA. (16) Carisma Therapeutics Inc, Philadelphia, PA, USA. (17) Carisma Therapeutics Inc, Philadelphia, PA, USA. (18) Carisma Therapeutics Inc, Philadelphia, PA, USA. (19) Carisma Therapeutics Inc, Philadelphia, PA, USA. (20) Carisma Therapeutics Inc, Philadelphia, PA, USA. (21) Carisma Therapeutics Inc, Philadelphia, PA, USA. (22) Carisma Therapeutics Inc, Philadelphia, PA, USA. (23) Carisma Therapeutics Inc, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (26) Carisma Therapeutics Inc, Philadelphia, PA, USA. (27) Carisma Therapeutics Inc, Philadelphia, PA, USA. (28) Carisma Therapeutics Inc, Philadelphia, PA, USA. (29) Carisma Therapeutics Inc, Philadelphia, PA, USA. (30) Carisma Therapeutics Inc, Philadelphia, PA, USA. (31) Carisma Therapeutics Inc, Philadelphia, PA, USA. michael.klichinsky@carismatx.com.

Citation: Nat Commun 2025 Jan 15 16:706 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39814734

Extracellular Vesicles Released by Glioblastoma Cancer Cells Drive Tumor Invasiveness via Connexin-43 Gap Junctions

Tags:

Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma

Tags:

Cross-priming in cancer immunology and immunotherapy

Tags:

Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics

Tags:

Ultrasound-Enhanced Spleen-Targeted mRNA Delivery via Fluorinated PEGylated Lipid Nanoparticles for Immunotherapy

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Infiltration and subtype analysis of CD3 + CD20 + T cells in lung cancer

Tags:

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer

Tags:

Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity Spotlight

Tags:

Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice Spotlight

Tags:

Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models Spotlight

Tags:

Extracellular Vesicles Released by Glioblastoma Cancer Cells Drive Tumor Invasiveness via Connexin-43 Gap Junctions

Tags:

Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma

Tags:

Cross-priming in cancer immunology and immunotherapy

Tags:

Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics

Tags:

Ultrasound-Enhanced Spleen-Targeted mRNA Delivery via Fluorinated PEGylated Lipid Nanoparticles for Immunotherapy

Tags:

Infiltration and subtype analysis of CD3 + CD20 + T cells in lung cancer

Tags:

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer

Tags:

Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity Spotlight

Tags:

Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice Spotlight

Tags:

Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models Spotlight

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