Journal Articles

ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype

We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1. Macrophage depletion with clodronate reduced the tumor-infiltrating effector CD4 and CD8 T cells, impairing their antitumor functions. Furthermore, the recruitment and polarization of M1-like macrophages required IFN-_. Therefore, in this study, we show that there is a positive feedback loop between intratumoral effector T cells and tumor-associated macrophages (TAMs), in which the IFN-_ produced by the T cells polarizes the TAMs into M1-like phenotype, and the TAMs, in turn, reshape the tumor microenvironment to facilitate T cell infiltration, immune function, and tumor rejection.

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center,

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center , Houston, TX, USA. ROR: https://ror.org/04twxam07 Immunotherapy Platform, James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ROR: https://ror.org/04twxam07 Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center , Houston, TX, USA. ROR: https://ror.org/04twxam07 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ROR: https://ror.org/04twxam07 (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center , Houston, TX, USA. ROR: https://ror.org/04twxam07 Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center , Houston, TX, USA. ROR: https://ror.org/04twxam07

Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3_anti-GD2 bispecific antibody armed T cells

BACKGROUND: The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3_anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. METHODS: The 3+3_dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160_10(6) GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m(2)) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m(2)). The phase II segment focused on patients with NB at the dose 3 level of 160_10(6) GD2BATs/kg/infusion. RESULTS: Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-_) EliSpots, Th1 cytokines, and/or chemokines. CONCLUSIONS: This study demonstrated the safety of GD2BATs up to 160_10(6)_cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.

Author Info: (1) St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA yankelevic@gmail.com LGL4F@uvahealth.org. Children's Hospital of Michigan, Detroit, Michigan, USA. (2)

Author Info: (1) St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA yankelevic@gmail.com LGL4F@uvahealth.org. Children's Hospital of Michigan, Detroit, Michigan, USA. (2) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (3) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (4) Children's Hospital of Michigan, Detroit, Michigan, USA. (5) Children's Hospital of Michigan, Detroit, Michigan, USA. (6) Children's Hospital of Michigan, Detroit, Michigan, USA. (7) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (8) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (9) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (10) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (11) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (12) Wistar Institute, Philadelphia, Pennsylvania, USA. (13) Karmanos Cancer Institute, Detroit, Michigan, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) University of Virginia Cancer Center, Charlottesville, Virginia, USA yankelevic@gmail.com LGL4F@uvahealth.org.

CD155 as an emerging target in tumor immunotherapy

CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape. In addition, novel therapeutic strategies and clinical trials targeting CD155 and its receptors are summarized, providing a strong rationale and way forward for the development of next-generation immunotherapies.

Author Info: (1) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of He

Author Info: (1) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (2) Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China. (3) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (4) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (5) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: yichaozheng@zzu.edu.cn. (6) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: liuhuimin@zzu.edu.cn.

The role of extracellular vesicle immune checkpoints in cancer

Immune checkpoints (ICPs) play a crucial role in regulating the immune response. In the tumor, malignant cells can hijack the immunosuppressive effects of inhibitory ICPs to promote tumor progression. Extracellular vesicles (EVs) are produced by a variety of cells and contain bioactive molecules on their surface or within their lumen. The expression of ICPs has also been detected on EVs. In vitro and in vivo studies have shown that extracellular vesicle immune checkpoints (EV ICPs) have immunomodulatory effects and are involved in tumor immunity. EV ICPs isolated from the peripheral blood of cancer patients are closely associated with the tumor progression and the prognosis of cancer patients. Blocking inhibitory ICPs has been recognized as an effective strategy in cancer treatment. However, the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment is hindered by the emergence of therapeutic resistance, which limit their widespread use. Researchers have demonstrated that EV ICPs are correlated with clinical response to ICIs therapy and were involved in therapeutic resistance. Therefore, it's essential to investigate the immunomodulatory effects, underlying mechanisms, and clinical significance of EV ICPs in cancer. This review aims to comprehensively explore these aspects. We have provided a comprehensive description of the cellular origins, immunomodulatory effects, and clinical significance of EV ICPs in cancer, based on relevant studies.

Author Info: (1) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (2) Department of Laborat

Author Info: (1) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (2) Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing Jiangsu, China. (3) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (4) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.

Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.

Author Info: (1) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (2) Prinses Maxima Centrum vo

Author Info: (1) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (2) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (3) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (4) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Center of Pediatric Hematology & Oncology, University of Catania, Catania, Italy. (5) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (6) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (7) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (8) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (9) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (10) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (11) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (12) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (13) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Oncode Institute, Utrecht, The Netherlands. (14) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (15) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (16) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (17) Center of Pediatric Hematology & Oncology, University of Catania, Catania, Italy. (18) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (19) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (20) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Department of Hematology, UMC Utrecht, Utrecht, The Netherlands. (21) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (22) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Oncode Institute, Utrecht, The Netherlands. (23) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (24) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (25) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (26) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands S.Nierkens-2@prinsesmaximacentrum.nl. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4(+) and CD8(+) T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

Author Info: (1) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Departmen

Author Info: (1) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (2) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. (3) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. (4) Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. (5) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (6) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (7) Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (8) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (9) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (10) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (11) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. (12) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (13) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. (14) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. (15) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: sdubinett@mednet.ucla.edu. (16) Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bliu@mednet.ucla.edu.

Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins

Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely-used strategy for cargo enrichment in EVs, which could compromise t the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodelling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.

Author Info: (1) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blo

Author Info: (1) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. (3) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (4) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (5) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (8) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. (9) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. (10) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. (11) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.

An IRF2-Expressing Oncolytic Virus Changes the Susceptibility of Tumor Cells to Antitumor T cells and Promotes Tumor Clearance

Interferon regulatory factor 1 (IRF1) can promote antitumor immunity. However, we have shown previously that in the tumor cell, IRF1 can promote tumor growth, and IRF1-deficient tumor cells exhibit severely restricted tumor growth in several syngeneic mouse tumor models. Here, we investigate the potential of functionally modulating IRF1 to reduce tumor progression and prolong survival. Using inducible IRF1 expression, we established that it is possible to regulate IRF1 expression to modulate tumor progression in established B16-F10 tumors. Expression of IRF2, which is a functional antagonist of IRF1, down-regulated IFN_-induced expression of inhibitory ligands, up-regulated MHC-related molecules, and slowed tumor growth and extended survival. We characterized the functional domain(s) of IRF2 needed for this antitumor activity, showing that a full-length IRF2 was required for its antitumor functions. Finally, using an oncolytic vaccinia virus as a delivery platform, we showed that IRF2-expressing vaccinia virus suppressed tumor progression and prolonged survival in multiple tumor models. These results suggest the potency of targeting IRF1 and using IRF2 to modulate immunotherapy.

Author Info: (1) University of Pittsburgh, Pittsburgh, PA, United States. (2) University of Pittsburgh, Pittsburgh, PA, United States. (3) University of Pittsburgh, Pittsburgh, PA, United State

Author Info: (1) University of Pittsburgh, Pittsburgh, PA, United States. (2) University of Pittsburgh, Pittsburgh, PA, United States. (3) University of Pittsburgh, Pittsburgh, PA, United States. (4) University of Pittsburgh, Pittsburgh, PA, United States. (5) University of Pittsburgh, Pittsburgh, PA, United States.

Melanoma extracellular vesicles inhibit tumor growth and metastasis by stimulating CD8 T cells

Tumor cell-derived extracellular vesicles (EVs) play a crucial role in mediating immune responses by carrying and presenting tumor antigens. Here, we suggested that melanoma EVs triggered cytotoxic CD8 T cell-mediated inhibition of tumor growth and metastasis. Our results indicated that immunization of mice with melanoma EVs inhibited melanoma growth and metastasis while increasing CD8 T cells and serum interferon _ (IFN-_) in vivo. In vitro experiments showed that melanoma EV stimulates dendritic cells (DCs) maturation, and mature dendritic cells induce T lymphocyte activation. Thus, tumor cell-derived EVs can generate anti-tumor immunity in a prophylactic setting and may be potential candidates for cell-free tumor vaccines.

Author Info: (1) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laborato

Author Info: (1) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (2) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (3) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (4) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (5) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; National Engineering Research Center of Ultrasound Medicine, Chongqing 401121, China. Electronic address: lqfang06@163.com. (6) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. Electronic address: sajinbai@cqmu.edu.cn.

cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors

Type I interferons (IFN-I) play pivotal roles in tumor therapy for three decades, underscoring the critical importance of maintaining the integrity of the IFN-1 signaling pathway in radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, the specific mechanism by which IFN-I contributes to these therapies, particularly in terms of activating dendritic cells (DCs), remains unclear. Based on recent studies, aberrant DNA in the cytoplasm activates the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling pathway, which in turn produces IFN-I, which is essential for antiviral and anticancer immunity. Notably, STING can also enhance anticancer immunity by promoting autophagy, inflammation, and glycolysis in an IFN-I-independent manner. These research advancements contribute to our comprehension of the distinctions between IFN-I drugs and STING agonists in the context of oncology therapy and shed light on the challenges involved in developing STING agonist drugs. Thus, we aimed to summarize the novel mechanisms underlying cGAS-STING-IFN-I signal activation in DC-mediated antigen presentation and its role in the cancer immune cycle in this review.

Author Info: (1) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (2) Fujian Key Labo

Author Info: (1) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (2) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (3) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (4) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (5) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. (6) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. shenyk@fjnu.edu.cn. (7) Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. chenqi@fjnu.edu.cn.

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