Journal Articles

IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity

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Yihan Zuo 1, David J Vohwinkel 1, Bowen Dong 2, James R McDowell 1, Brandon V Guzman 1, Tharuna Sri Manickavel Pandian 2, Saborni Chattopadhyay 2, A J R McGray 2, Scott H Olejniczak 2, Joyce Ohm 3, Jianmin Wang 4, Mark D Long 4, Eduardo Cortes Gomez 4, Terence J Purdon 1, Wei Luo 5, Hemn Mohammadpour 6, Christopher S Hackett 7, Leonid Cherkassky 8, Marco Davila 1, Scott I Abrams 9, Renier J Brentjens 10

Cancer Cell

Zuo et al. assessed the efficacy of IL-36γ-armored DLL3- and GD3-dual-targeting CAR T cells across various tumor models. ​Dual-targeting CAR-T were more efficacious than single-targeting CAR-T, and the addition of IL-36γ armoring further improved efficacy. The IL-36γ-armored CAR-T treatment, with or without prior lymphodepletion, resulted in reprogramming of neutrophils in the TME. Neutrophils obtained antigen-presenting functionality, leading to epitope spreading and the induction of endogenous antitumor T cell responses to non-CAR-targeted tumor antigens.

Yihan Zuo 1, David J Vohwinkel 1, Bowen Dong 2, James R McDowell 1, Brandon V Guzman 1, Tharuna Sri Manickavel Pandian 2, Saborni Chattopadhyay 2, A J R McGray 2, Scott H Olejniczak 2, Joyce Ohm 3, Jianmin Wang 4, Mark D Long 4, Eduardo Cortes Gomez 4, Terence J Purdon 1, Wei Luo 5, Hemn Mohammadpour 6, Christopher S Hackett 7, Leonid Cherkassky 8, Marco Davila 1, Scott I Abrams 9, Renier J Brentjens 10

Cancer Cell

Zuo et al. assessed the efficacy of IL-36γ-armored DLL3- and GD3-dual-targeting CAR T cells across various tumor models. ​Dual-targeting CAR-T were more efficacious than single-targeting CAR-T, and the addition of IL-36γ armoring further improved efficacy. The IL-36γ-armored CAR-T treatment, with or without prior lymphodepletion, resulted in reprogramming of neutrophils in the TME. Neutrophils obtained antigen-presenting functionality, leading to epitope spreading and the induction of endogenous antitumor T cell responses to non-CAR-targeted tumor antigens.

ABSTRACT: Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicate primary solid tumors and enable rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulate the TME and reprogram unique neutrophil subsets with tumoricidal ability and antigen-(cross) presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.

Author Info: 1- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 2- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 1426

Author Info: 1- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 2- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 3- Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 4- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 5- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 6- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 7- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. 8- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA. 9- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: Scott.Abrams@RoswellPark.org. 10- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: renier.brentjens@roswellpark.org.

Citation: Cancer cell 2025 Dec 11

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/41386225/

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Drilling dendritic cell activation- Engineering interfacial mechano-biochemical cues for enhanced immunotherapy

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Yali Ming (1,2); Jinji Wei (1,2); Zhaoyi Zhai (1,2); Zifeng Meng (3); Xiaonan Huang (1,2); Yuning Hu (1); Qi Huang (3); Guanghui Ma (1,2); Yufei Xia (1,2,4).

Cell Biomaterials

Ming et al. generated oil-water emulsions stabilized by alum particles (ASPEs) to mechanically activate DCs. Increasing alum crystallinity increased ASPE interfacial stiffness, in turn increasing DC contact area, membrane tension, and internalization, leading to PIEZO1-induced calcium flux and MAPK activation, altogether improving DC activation. Admixed with Ag, ASPEs induced a stronger Th1 responses in C57 mice compared to standard alum, increasing with ASPE stiffness. A high-stiffness ASPE incorporating MPLA adjuvant also induced strong, Th1-biased immune responses and improved efficacy over MPLA alone when used to prepare a DC vaccine.

Contributed by Alex Najibi

Yali Ming (1,2); Jinji Wei (1,2); Zhaoyi Zhai (1,2); Zifeng Meng (3); Xiaonan Huang (1,2); Yuning Hu (1); Qi Huang (3); Guanghui Ma (1,2); Yufei Xia (1,2,4).

Cell Biomaterials

Ming et al. generated oil-water emulsions stabilized by alum particles (ASPEs) to mechanically activate DCs. Increasing alum crystallinity increased ASPE interfacial stiffness, in turn increasing DC contact area, membrane tension, and internalization, leading to PIEZO1-induced calcium flux and MAPK activation, altogether improving DC activation. Admixed with Ag, ASPEs induced a stronger Th1 responses in C57 mice compared to standard alum, increasing with ASPE stiffness. A high-stiffness ASPE incorporating MPLA adjuvant also induced strong, Th1-biased immune responses and improved efficacy over MPLA alone when used to prepare a DC vaccine.

Contributed by Alex Najibi

ABSTRACT: A key challenge in immunotherapy is enhancing immune responses without introducing new molecular entities that trigger regulatory hurdles. While the size, shape, and composition of approved adjuvants have been optimized, their mechanical properties remain underexplored. Here, we repurpose approved aluminum-based adjuvants (alum) by engineering alum-stabilized Pickering emulsions (ASPEs) to synergize mechanical (PIEZO1) and biochemical (TLR4) cues. ASPEs, featuring interfacial alum with optimal rigidity, were heralded to promote an enlarged contact area with dendritic cells (DCs) during endocytosis, transmitting localized stress that activates PIEZO1-mediated calcium/mitogen-activated protein kinase (MAPK) signaling. This enhances antigen cross-presentation and Th1 immunity. Co-delivering a TLR4 agonist (monophosphoryl lipid A [MPLA]) further boosted immunogenicity in a varicella-zoster virus vaccine among aged mice, outperforming alum+MPLA (AS04). In antigen-pulsed DC therapy combined with PD-1 blockade, ASPE-M-treated DCs achieved a 2.11-fold greater tumor suppression compared with tumor lysate-M-based clinical approaches. These findings demonstrate how tuning the interfacial mechanics of approved materials can unlock mechano-immunotherapy with translational potential.

Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China (2) University of

Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China (2) University of Chinese Academy of Sciences, Beijing 100049, P.R. China (3) Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, P.R. China (4) Lead contact

Citation: Cell Biomaterial Dec 10, 2025

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Predicability of PD-L1 expression in cancer cells based solely on H&E-stained sections

(1) Faa G (2) Fraschini M (3) Ziranu P (4) Pretta A (5) Porcu G (6) Saba L (7) Scartozzi M (8) Shokun N (9) Rugge M

Journal of pathology informatics | Free PMC Article

(1) Faa G (2) Fraschini M (3) Ziranu P (4) Pretta A (5) Porcu G (6) Saba L (7) Scartozzi M (8) Shokun N (9) Rugge M

Journal of pathology informatics | Free PMC Article

PD-L1 expression is an important biomarker for selecting patients who are eligible for immune checkpoint inhibitor (ICI) therapy. However, evaluating PD-L1 through immunohistochemistry often faces significant interobserver variability and requires considerable time and resources. Recent advancements in artificial intelligence (AI) have transformed the field of pathology, leading to more standardized and reproducible methods for biomarker quantification. In this study, we examine the application of AI-driven models, particularly deep learning algorithms, to predict PD-L1 expression directly from hematoxylin and eosin-stained histological slides. Several AI-based approaches have been studied, demonstrating high accuracy in estimating PD-L1 expression and predicting responses to ICIs across various cancer types. AI-driven assessments of PD-L1 have been shown to reduce the subjectivity associated with manual scoring methods, such as the Tumor Proportion Score and the Combined Positive Score. Moreover, integrating AI with multimodal data, including genomics, radiomics, and real-world clinical data, can further enhance predictive accuracy and improve patient stratification for immunotherapy. Finally, AI-driven computational pathology offers a transformative approach to biomarker evaluation, providing a faster, more objective, and cost-effective alternative to traditional methods, with significant implications for personalized oncology and precision medicine. Despite these promising results, several challenges remain to be addressed, such as the need for large-scale validation, standardization of AI models, and regulatory approvals for clinical implementation. Tackling these issues will be crucial for incorporating AI-based PD-L1 assessments into routine pathology workflows.

Author Info: (1) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. Department of Biology, College of Science and Technology, Temple Un

Author Info: (1) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA. (2) Department of Electrical and Electronic Engineering, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (3) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (4) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (5) Department of Pathology, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy. (6) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (7) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (8) National Cancer Institute, Kyiv, Ukraine. Associazione "Angela Serra" per la ricerca sul cancro, Modena, Italy. (9) Department of Medicine - DIMED; General Anatomic Pathology and Cytopathology Unit, Universitˆ degli Studi di Padova, 35121 Padova, Italy.

Citation: J Pathol Inform 2025 Nov 19:100524 Epub10/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41340634

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mRNA-engineered T lymphocytes secreting bispecific T cell engagers with therapeutic potential in solid tumors

(1) Zagorac I (2) Ram’rez-Fern‡ndez ç (3) Tapia-Galisteo A (4) Rubio-PŽrez L (5) G—mez-Rosel M (6) Grau M (7) Rodr’guez-Peralto JL (8) çlvarez-Vallina L (9) Blanco B

Frontiers in immunology | Free PMC Article

(1) Zagorac I (2) Ram’rez-Fern‡ndez ç (3) Tapia-Galisteo A (4) Rubio-PŽrez L (5) G—mez-Rosel M (6) Grau M (7) Rodr’guez-Peralto JL (8) çlvarez-Vallina L (9) Blanco B

Frontiers in immunology | Free PMC Article

BACKGROUND: In the last decade, chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of hematologic malignancies. However, antitumor responses in solid tumors remain poor, and the difficulty in finding truly tumor-specific target antigens leads to a high risk of on-target/off-tumor toxicity. Transient modification with mRNA is gaining momentum as an alternative approach to viral transduction in order to achieve a better safety profile. On the other hand, generation of T cells secreting bispecific T cell engagers (TCEs) has been reported to outperform the antitumor efficacy of T lymphocytes expressing membrane-anchored CARs, due to the ability of the soluble TCEs to recruit unmodified bystander T cells. METHODS: We have electroporated human primary T cells with in vitro transcribed mRNA encoding an anti-EGFR x anti-CD3 bispecific T cell engager. Such mRNA-modified T cells (STAR(EGFR)-T cells) have been analyzed for anti-EGFR bispecific TCE secretion and for their ability to drive anti-tumor responses against EGFR-expressing cells, both in vitro and in vivo. RESULTS: STAR(EGFR)-T cells transiently secrete bispecific TCEs capable of redirecting T lymphocytes to exert tumor cell-specific killing in in vitro assays. Moreover, STAR(EGFR)-T cells efficiently control tumor growth in in vivo xenograft models of solid malignancy. CONCLUSIONS: Our results strongly support mRNA-engineered TCE-secreting T cells as a promising therapeutic strategy for solid tumors.

Author Info: (1) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n San

Author Info: (1) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (2) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. (3) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (4) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (5) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (6) Animal Facility, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. (7) Department of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain. Department of Pathology, Universidad Complutense, Madrid, Spain. Cutaneous Oncology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red en Oncolog’a (CIBERONC), Madrid, Spain. (8) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. Banc de Sang i Teixits, Barcelona, Spain. (9) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain.

Citation: Front Immunol 2025 16:1684655 Epub11/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41341587

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Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity

(1) Margulies D (2) Jiang J (3) Panda A (4) Natarajan K (5) Lei H (6) Sharma S (7) Boyd L (8) Towler R (9) Chempati S (10) Ahmad J (11) Morton A (12) Lang Z (13) Sun Y (14) Sgourakis N (15) Meier-Schellersheim M (16) Huang R (17) Shevach E

Research square | Free PMC Article

(1) Margulies D (2) Jiang J (3) Panda A (4) Natarajan K (5) Lei H (6) Sharma S (7) Boyd L (8) Towler R (9) Chempati S (10) Ahmad J (11) Morton A (12) Lang Z (13) Sun Y (14) Sgourakis N (15) Meier-Schellersheim M (16) Huang R (17) Shevach E

Research square | Free PMC Article

Anti-major histocompatibility complex class I (MHC-I) mAbs can stimulate immune responses to tumors and infections by blocking suppressive signals delivered via various immune inhibitory receptors. To understand such functions, we determined the structure of a highly cross-reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural models determined by the two methods were essentially identical revealing that B1.23.2 binds a conserved region on the _21 helix that overlaps the killer immunoglobulin-like receptor (KIR) binding site. Structural comparison to KIR/HLA complexes reveals a mechanism by which B1.23.2 blocks inhibitory receptor interactions, leading to natural killer (NK) cell activation. B1.23.2 treatment of the human KLM-1 pancreatic cancer model in humanized (NSG-IL15) mice provides evidence of suppression of tumor growth. Such anti-MHC-I mAb that block inhibitory KIR/HLA interactions may prove useful for tumor immunotherapy.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17)

Citation: Res Sq 2025 Oct 31 Epub10/31/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41333432

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Discovery of a small molecule TLR3 agonist adjuvant

(1) Lee B (2) Dong D (3) Nanishi E (4) Awad JM (5) Abedi KZ (6) Saito Y (7) Borriello F (8) Barman S (9) Brook B (10) Kelly A (11) Menon M (12) Marques-Mourlet C (13) Gupta MV (14) Lister I (15) Oh C (16) Lyskawa K (17) Goetz M (18) Walker K (19) Cheng WK (20) Brightman SE (21) Sharma P (22) O'Meara TR (23) Chew K (24) Vieira D (25) Ryff K (26) Sweitzer C (27) Thomas S (28) van Haren SD (29) Pettengill M (30) Seo HS (31) Dhe-Paganon S (32) Zhang W (33) Levy O (34) Dowling DJ

Nature communications

(1) Lee B (2) Dong D (3) Nanishi E (4) Awad JM (5) Abedi KZ (6) Saito Y (7) Borriello F (8) Barman S (9) Brook B (10) Kelly A (11) Menon M (12) Marques-Mourlet C (13) Gupta MV (14) Lister I (15) Oh C (16) Lyskawa K (17) Goetz M (18) Walker K (19) Cheng WK (20) Brightman SE (21) Sharma P (22) O'Meara TR (23) Chew K (24) Vieira D (25) Ryff K (26) Sweitzer C (27) Thomas S (28) van Haren SD (29) Pettengill M (30) Seo HS (31) Dhe-Paganon S (32) Zhang W (33) Levy O (34) Dowling DJ

Nature communications

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-_B activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally to female mice, PVP-057 enhances long-term humoral immunogenicity of varicella-zoster virus glycoprotein E to levels comparable to those induced by the clinical grade standard benchmark adjuvant, AS01B, while concurrently inducing cell-mediated immunity. To demonstrate the large-scale and precise synthesis necessary for the efficient mass production of a small molecule agonist, a green chemistry approach was completed, devising a three-step, 24-hour synthesis scheme for PVP-057, with a reliable purity of ~98%. Featuring highly efficient and scalable synthesis, a distinct TLR3-dependent mechanism of action, and robust adjuvanticity, the PVP-057 pharmacophore has prophylactic and therapeutic potential.

Author Info: (1) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (2) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (3) Precision Vaccines Pro

Author Info: (1) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (2) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (3) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (4) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA. (5) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (6) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (7) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Generate Biomedicines, Somerville, MA, USA. (8) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (9) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (10) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (11) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (12) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (13) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (14) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (15) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (16) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (17) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (18) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (19) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (20) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (21) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (22) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (23) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (24) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (25) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (26) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. (27) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (28) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. (29) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA. (30) Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. (31) Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. (32) Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA. (33) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Broad Institute of MIT & Harvard, Cambridge, MA, USA. (34) Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA. David.Dowling@childrens.harvard.edu. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. David.Dowling@childrens.harvard.edu.

Citation: Nat Commun 2025 Dec 4 Epub12/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41339634

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Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy

(1) Wong JKM (2) Lam PY (3) Coleborn E (4) Jose J (5) Alim L (6) Tu C (7) Antczak M (8) Dietmair B (9) Hagh AG (10) Noronha L (11) Cheetham SW (12) Hooper J (13) Beavis PA (14) Merino D (15) Berthelet J (16) Aoude LG (17) McCart-Reed AE (18) Lakhani S (19) Simpson PT (20) Rossi GR (21) Brooks AJ (22) Jones ML (23) Simpson F (24) Souza-Fonseca-Guimaraes F

Molecular therapy

(1) Wong JKM (2) Lam PY (3) Coleborn E (4) Jose J (5) Alim L (6) Tu C (7) Antczak M (8) Dietmair B (9) Hagh AG (10) Noronha L (11) Cheetham SW (12) Hooper J (13) Beavis PA (14) Merino D (15) Berthelet J (16) Aoude LG (17) McCart-Reed AE (18) Lakhani S (19) Simpson PT (20) Rossi GR (21) Brooks AJ (22) Jones ML (23) Simpson F (24) Souza-Fonseca-Guimaraes F

Molecular therapy

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an emerging target in cancer immunotherapy, recognized for its consistent and elevated expression across several epithelial tumors, including triple-negative breast cancer (TNBC). TNBC is an aggressive and difficult-to-treat cancer, with limited effective therapeutic options currently available. Therapeutic approaches centered on targeting ROR1 have therefore become increasingly popular, with ROR1 chimeric antigen receptor (CAR) T cells currently in clinical trials to treat TNBC patients. While ROR1-targeting therapies have shown promising preclinical results, single arm treatment has often shown low efficacy as well as off-target toxicity. Natural killer (NK) cell-based immunotherapies, such as antibody-dependent cell cytotoxicity-inducing monoclonal antibodies and CAR NK cells, have also been shown to induce cancer cell cytotoxicity; however, with less toxicity compared with CAR T cells. Here, we developed and characterized a phage-derived single-chain fragment variable (scFv) against a highly specific ROR1 region and generated scFv-derived chimeric monoclonal antibodies and anti-ROR1-CAR NK cells, which show anti-cancer efficacy against TNBC cells. Additionally, we found TGF-_ inhibition using either small-molecule inhibitors or CRISPR-Cas9-edited NK cells could further enhance ROR1-targeting therapy persistence and efficacy in controlling TNBC tumor growth.

Author Info: (1) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (2) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (3)

Author Info: (1) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (2) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (3) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (4) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (5) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (6) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (7) Queensland Cyber Infrastructure Foundation Ltd (QCIF) Bioinformatics, Brisbane, QLD 4072, Australia. (8) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia; BASE Facility, University of Queensland, St Lucia, QLD 4067, Australia. (9) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia. (10) Laborat—rio de Patologia Experimental, Curitiba, Queensland 80215-901, Brazil. (11) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia; BASE Facility, University of Queensland, St Lucia, QLD 4067, Australia. (12) Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia. (15) Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia. (16) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (17) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia. (18) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia. (19) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia; School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Saint Lucia, QLD 4067, Australia. (20) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (21) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; School of Science & Technology, University of New England, Armidale NSW 2351, Australia. (22) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia. (23) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (24) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. Electronic address: f.guimaraes@uq.edu.au.

Citation: Mol Ther 2025 Dec 2 Epub12/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41338184

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Structure guided analysis of KRAS G12 mutants in HLA-A*11:01 reveals a length encoded immunogenic advantage in G12D

(1) Zhu J (2) Chen Z (3) Xu X (4) Wang Y (5) Liu P (6) Wen M (7) Wang Q (8) He Y (9) Jin H (10) Xue H (11) Wang S (12) Xu K (13) Zhao L

Communications biology

(1) Zhu J (2) Chen Z (3) Xu X (4) Wang Y (5) Liu P (6) Wen M (7) Wang Q (8) He Y (9) Jin H (10) Xue H (11) Wang S (12) Xu K (13) Zhao L

Communications biology

KRAS G12 mutations are frequent oncogenic drivers, yet their differential immunogenicity complicates T cell-based therapies. Here, we integrate structural, biophysical, and functional analyses to examine how KRAS G12 variants remodel peptide-MHC-I (pMHC) architecture and T cell receptor (TCR) recognition. Using HLA-A*11:01, we show that single residue substitutions at position 12 induce distinct conformational changes in the MHC groove, with G12D uniquely destabilizing the complex through a buried aspartate side chain. Notably, G12D peptides adopt two registers, a 9-mer and a 10-mer, that diverge sharply in structure and immunogenicity. The 10-mer forms a compact, stable pMHC with a TCR-accessible surface, while the 9-mer adopts a bent conformation incompatible with recognition. Molecular dynamics and NMR titration confirm the superior stability and binding affinity of the 10-mer. These results highlight how peptide length and conformation critically shape immune visibility, offering mechanistic insight for optimizing TCR-T therapies against elusive neoantigens like KRAS G12D.

Author Info: (1) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (2) Department of Anesthesiology, Putuo People's Hospital, School

Author Info: (1) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (2) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (3) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (4) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (5) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. (6) Hangzhou Weizhi Biotechnology Co., Ltd, Hangzhou, China. (7) Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China. (8) Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. (9) State key laboratory of natural and biomimetic drugs, Peking University Health Science Center, Beijing, China. (10) National Facility for Protein Science in Shanghai, ZhangJiang lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China. (11) Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China. (12) Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. kx2129@tongji.edu.cn. (13) Department of Anesthesiology, Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China. lzhao@tongji.edu.cn.

Citation: Commun Biol 2025 Dec 3 Epub12/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41339521

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IL-12 and GM-CSF engineered dendritic cells enhance the enrichment and selection of tumor-reactive T cells for cancer immunotherapy

(1) Liu Z (2) Li H (3) Gao Z (4) Cheng R (5) Lu J (6) Che X (7) Dong J (8) Wang Z (9) Cui Z (10) Gu J (11) Bai Y (12) Li C (13) Liu Y (14) Wang C (15) Deng H

Frontiers in immunology | Free PMC Article

(1) Liu Z (2) Li H (3) Gao Z (4) Cheng R (5) Lu J (6) Che X (7) Dong J (8) Wang Z (9) Cui Z (10) Gu J (11) Bai Y (12) Li C (13) Liu Y (14) Wang C (15) Deng H

Frontiers in immunology | Free PMC Article

The use of tumor-reactive T cells in targeted tumor elimination holds significant potential for cancer immunotherapy, such as Tumor-Infiltrating Lymphocyte (TIL) therapy and TCR-T adoptive immunotherapy. Critical aspects of the effective clinical application of these immunotherapies include the enrichment and selection of tumor antigens and their corresponding reactive T cells. However, current in vitro methods for expanding and screening tumor antigen-reactive T cells remain inefficient. One reason for this inefficiency is the dysfunctional state of tumor-reactive T cells, which limits their expansion and activation. To address this challenge, we developed an optimized dendritic cell-based culture system, in which dendritic cells simultaneously express interleukin-12 and granulocyte-macrophage colony-stimulating factor (12GM-DCs), to enhance the expansion of tumor-reactive T cells. We found that 12GM-DCs can enrich reactive T cells targeting various tumor antigens, including virus-associated tumor antigens, tumor-associated antigens, mutant tumor neoantigens, and patient-specific tumor neoantigens. Moreover, 12GM-DCs increased the proportion of antigen-specific T cells, enhanced the activation of those T cells, and promoted the maintenance of a memory phenotype. The cytotoxicity of these antigen-reactive T cells was increased after co-culture with 12GM-DCs, likely due to the increased secretion of interferon-_ and granzyme B. Importantly, these functions and phenotypic advantages of tumor antigen-reactive T cells derived from the 12GM-DC culture system could be effectively maintained and the antitumor activity was also enhanced in tumor-burden mice. Our 12GM-DC coculture system effectively enriches antigen-specific T cells and has the potential to advance the clinical application of cancer immunotherapy by targeting tumor antigens and their reactive T cells.

Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (2) Depa

Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (2) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. (3) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (4) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (5) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (6) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (7) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (8) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (9) School of Life Sciences, Peking University, Beijing, China. (10) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (11) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (12) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (13) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (14) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. School of Life Sciences, Peking University, Beijing, China. (15) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing, China. Changping Laboratory, MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

Citation: Front Immunol 2025 16:1684842 Epub11/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41333469

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Scalable Exosome Isolation Platform for Clinical-Scale Therapeutics: Bridging Gaps in Drug Delivery and Regenerative Medicine

(1) Praween N (2) Guru KTP (3) Basu PK

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

(1) Praween N (2) Guru KTP (3) Basu PK

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

Exosomes are essential for facilitating intercellular communication. The importance of these molecules lies in the fact that they can transport bioactive molecules across cells, influencing critical physiological processes such as immune responses, tissue repair, and cell proliferation. In addition to their physiological roles, exosomes are also involved in various pathological conditions, including carcinoma, respiratory, neurodegeneration and cardiovascular diseases. They can convey signals that may promote tumor growth, metastasis, or immune evasion in cancer. This study suggests a unique scalable platform for effective exosome isolation based on functionalised SiO(2) wafers. Gold nanoparticles (GNPs) with diameters of 20 nm and 60 nm were synthesized and deposited on SiO(2) wafers before being PEGylated and conjugated with antibodies. The platform successfully isolated exosomes employing antibodies against CD9, CD81, and CD63, with CD63-coated wafers providing the most exosomes, in accordance with their abundance on the exosomal surface. NTA revealed the presence of exosomes. A 1 cm x 1 cm SiO(2) wafers successfully isolated 3.3 x 10(8) exosomes from 100 µL serum. A 2 cm x 2 cm wafer demonstrated a significant increase in isolation efficiency, capturing 7.2 x 10(8) exosomes from 200 µL serum, highlighting the scalability and potential for high-throughput exosome isolation using this platform. The average size of isolated exosomes ranged from 40 to 150 nm. This scalable technology offers a promising alternative to ultracentrifugation for exosome isolation. It has potential uses in the delivery of drugs and other biomedical fields.Clinical Relevance- This work enables scalable exosome isolation, critical for advancing therapies in drug delivery, neurodegenerative diseases, cancer, and regenerative medicine.

Author Info: (1) (2) (3)

Author Info: (1) (2) (3)

Citation: Annu Int Conf IEEE Eng Med Biol Soc 2025 Jul 2025:1-4 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41337068

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