Journal Articles

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells

Dendritic cells (DCs) are a heterogenous population of professional antigen presenting cells whose main role is diminished in a variety of malignancies, including cancer, leading to ineffective immune responses. Those mechanisms are inhibited due to the immunosuppressive conditions found in the tumor microenvironment (TME), where myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells known to play a key role in tumor immunoevasion by inhibiting T-cell responses, are extremely accumulated. In addition, it has been demonstrated that MDSCs not only suppress DC functions, but also their maturation and development within the myeloid linage. Considering that an increased number of DCs as well as the improvement in their functions boost antitumor immunity, DC-based vaccines were developed two decades ago, and promising results have been obtained throughout these years. Therefore, the remodeling of the TME promoted by DC vaccination has also been explored. Here, we aim to review the effectiveness of different DCs-based vaccines in murine models and cancer patients, either alone or synergistically combined with other treatments, being especially focused on their effect on the MDSC population.

Author Info: (1) Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Seville, Spain. Medical Oncology Service, Virgen Macarena University Hospit

Author Info: (1) Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Seville, Spain. Medical Oncology Service, Virgen Macarena University Hospital, Seville, Spain. (2) Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Seville, Spain. Department of Laboratory Medicine, Virgen Macarena University Hospital, Seville, Spain. (3) Laboratorio de Tecnolog’a Inmunol—gica, Facultad de Bioqu’mica y Ciencias Biol—gicas, Universidad Nacional del Litoral, Santa Fe capital, Argentina. (4) Laboratorio de CŽlulas Presentadoras de Ant’geno y Respuesta Inflamatoria, Instituto de Medicina Experimental (IMEX) - CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina. (5) Medical Oncology Service, Virgen Macarena University Hospital, Seville, Spain. (6) Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Seville, Spain. Department of Laboratory Medicine, Virgen Macarena University Hospital, Seville, Spain.

In situ vaccination with cowpea mosaic virus elicits systemic antitumor immunity and potentiates immune checkpoint blockade

BACKGROUND: In situ vaccination (ISV) is a cancer immunotherapy strategy in which immunostimulatory reagents are introduced directly into a tumor to stimulate antitumor immunity both against the treated tumor and systemically against untreated tumors. Recently, we showed that cowpea mosaic virus (CPMV) is a potent multi-toll-like receptor (TLR) agonist with potent efficacy for treating tumors in mice and dogs by ISV. However, ISV with CPMV alone does not uniformly treat all mouse tumor models tested, however this can be overcome through strategic combinations. More insight is needed to delineate potency and mechanism of systemic antitumor immunity and abscopal effect. METHOD: We investigated the systemic efficacy (abscopal effect) of CPMV ISV with a two-tumor mouse model using murine tumor lines B16F10, 4T1, CT26 and MC38. Flow cytometry identified changes in cell populations responsible for systemic efficacy of CPMV. Transgenic knockout mice and depleting antibodies validated the role of relevant candidate cell populations and cytokines. We evaluated these findings and engineered a multicomponent combination therapy to specifically target the candidate cell population and investigated its systemic efficacy, acquired resistance and immunological memory in mouse models. RESULTS: ISV with CPMV induces systemic antitumor T-cell-mediated immunity that inhibits growth of untreated tumors and requires conventional type-1 dendritic cells (cDC1s). Furthermore, using multiple tumor mouse models resistant to anti-programmed death 1 (PD-1) therapy, we tested the hypothesis that CPMV along with local activation of antigen-presenting cells with agonistic anti-CD40 can synergize and strengthen antitumor efficacy. Indeed, this combination ISV strategy induces an influx of CD8(+) T cells, triggers regression in both treated local and untreated distant tumors and potentiates tumor responses to anti-PD-1 therapy. Moreover, serial ISV overcomes resistance to anti-PD-1 therapy and establishes tumor-specific immunological memory. CONCLUSIONS: These findings provide new insights into in situ TLR activation and cDC1 recruitment as effective strategies to overcome resistance to immunotherapy in treated and untreated tumors.

Author Info: (1) Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA. (2) Bioengineering, University of California San Diego, La Jolla, Califor

Author Info: (1) Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA. (2) Bioengineering, University of California San Diego, La Jolla, California, USA. (3) Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA. (4) Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA. (5) Department of Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Fiering@dartmouth.edu nsteinmetz@ucsd.edu. (6) Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA Fiering@dartmouth.edu nsteinmetz@ucsd.edu. Geisel School of Medicine at Dartmouth, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA.

DNA origami-based artificial antigen-presenting cells for adoptive T cell therapy

Nanosized artificial antigen-presenting cells (aAPCs) with efficient signal presentation hold great promise for in vivo adoptive cell therapy. Here, we used DNA origami nanostructures as two-dimensional scaffolds to regulate the spatial presentation of activating ligands at nanoscale to construct high-effective aAPCs. The DNA origami-based aAPC comprises costimulatory ligands anti-CD28 antibody anchored at three vertices and T cell receptor (TCR) ligands peptide-major histocompatibility complex (pMHC) anchored at three edges with varying density. The DNA origami scaffold enables quantitative analysis of ligand-receptor interactions in T cell activation at the single-particle, single-molecule resolution. The pMHC-TCR-binding dwell time is increased from 9.9 to 12.1 s with increasing pMHC density, driving functional T cell responses. In addition, both in vitro and in vivo assays demonstrate that the optimized DNA origami-based aAPCs show effective tumor growth inhibiting capability in adoptive immunotherapy. These results provide important insights into the rational design of molecular vaccines for cancer immunotherapy.

Author Info: (1) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell T

Author Info: (1) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. (2) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. (3) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. (4) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. (5) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. (6) School of Chemistry and Chemical Engineering, and Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China. (7) Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein

Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8(+) T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2R_ with higher affinity, triggers STAT5 activation, and drives CD8(+) T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

Author Info: (1) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (2) Division of Cell Signaling and Immunology, School of Life Sciences, Uni

Author Info: (1) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (2) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (3) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (4) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (5) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. UniversitŽ de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France. (6) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK. (7) Structural Biology and NMR Laboratory, Linderstr¿m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark. (8) Department of Biology/Chemistry and Center for Cellular Nanoanalytics (CellNanOs), OsnabrŸck University, Barbarastr. 11, 49076 OsnabrŸck, Germany. (9) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (10) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK. (11) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (12) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (13) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (14) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (15) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France. (16) CNRS/IIS/Centre Oscar Lambret/Lille University SMMiL-E Project, CNRS DŽlŽgation Hauts-de-France, Lille, France. CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, Tokyo, Japan. (17) Department of Biology/Chemistry and Center for Cellular Nanoanalytics (CellNanOs), OsnabrŸck University, Barbarastr. 11, 49076 OsnabrŸck, Germany. (18) Structural Biology and NMR Laboratory, Linderstr¿m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark. (19) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK. (20) Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK. (21) Inserm UMR1277, CNRS UMR9020-CANTHER, UniversitŽ de Lille, Lille University Hospital, Lille, France.

Single-cell fate mapping reveals widespread clonal ignorance of low- affinity T cells exposed to systemic infection

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen-specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single-cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high-affinity antigen- specific CD8(+) T cells are efficiently recruited upon systemic infection. In contrast, most low- affinity antigen-specific T cells ignore the priming antigen and persist in the na•ve state while remaining fully responsive to subsequent immunization with a high-affinity ligand. These data establish the widespread clonal ignorance of low-affinity T cells as a major factor shaping the composition of antigen-specific CD8(+) T cell responses to systemic infection. This article is protected by copyright. All rights reserved.

Author Info: (1) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (2) Institute for Medical Microbiology, Immunology and Hygien

Author Info: (1) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (2) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (3) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (4) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (5) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. German Center for Infection Research (DZIF), Partner site Munich, Germany. (6) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany. (7) Institute for Medical Microbiology, Immunology and Hygiene, Technische UniversitŠt MŸnchen (TUM), Munich, Germany.

Post-transplant cyclophosphamide for GVHD prophylaxis in pediatrics with chronic active Epstein-Barr virus infection after haplo-HSCT

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is a rare but life-threatening progressive disease. Human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is the best choice as sometimes HLA-matched donor is not accessible. However, graft-versus-host-disease (GVHD) following transplantation remains a major cause of treatment failure and elevated mortality. Post-transplant cyclophosphamide (PTCy) has recently emerged for effective GVHD prophylaxis in a haploidentical setting in many hematologic malignancies. Here, we report the performance of PTCy for GVHD prophylaxis in a series of CEABV patients treated with haplo-HSCT. METHODS: Consecutive pediatric CAEBV patients who were treated with haplo-HSCT and give PTCy for GVHD prophylaxis were analyzed. 1-year GVHD and relapse-free survival (GRFS), overall survival (OS) and cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) were estimated. RESULTS: A total of 8 patients ranging from 2 to 15 years old were included. Among them, 4 patients had early complications after haplo-HSCT. Counts of T-cell subsets increased within 6 months post transplantation, indicating an immune reconstitution. Only 1 patient developed grade II acute GVHD, and 2 patients had moderate cGVHD. One patient died from diffuse alveolar hemorrhage within the first year after transplantation. The 1-year GRFS rate, OS rate and cumulative incidence of moderate-to-severe cGVHD were 62.5%, 87.5% and 25.0%, respectively. CONCLUSION: Our findings suggest that, among CAEBV patients treated with haplo-HSCT, PTCy may be an alternative choice for the prevention of GVHD.

Author Info: (1) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (2) Department of Hematology, Aerospace Center Hospital, No.

Author Info: (1) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (2) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (3) Department of Hematology, Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing, 100700, China. (4) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (5) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (6) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. (7) Department of Hematology, Aerospace Center Hospital, No. 15, Yuquan Road, Haidian District, Beijing, 100049, China. wangjingbo721@126.com.

Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.

Author Info: (1) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Re

Author Info: (1) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. Department of Frontier Research in Tumor Immunology, Center of Medical Innovation and Translational Research, Graduate School of Medicine, Osaka University, Osaka, Japan. (2) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. (3) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (4) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. Institute of Research in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico. (5) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (6) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (7) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (8) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (9) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (10) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (11) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (12) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (13) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (14) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (15) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. (16) Institute for Protein Research, Osaka University, Suita, Japan. (17) Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh, UK. (18) Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan. (19) Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (20) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (21) Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.

CD47 cross-dressing by extracellular vesicles expressing CD47 inhibits phagocytosis without transmitting cell death signals

Transgenic CD47 overexpression is an encouraging approach to ameliorating xenograft rejection and alloresponses to pluripotent stem cells, and the efficacy correlates with the level of CD47 expression. However, CD47, upon ligation, also transmits signals leading to cell dysfunction or death, raising a concern that overexpressing CD47 could be harmful. Here, we unveiled an alternative source of cell surface CD47. We showed that extracellular vesicles, including exosomes, released from normal or tumor cells overexpressing CD47 (transgenic or native) can induce efficient CD47 cross-dressing on pig or human cells. Like the autogenous CD47, CD47 cross-dressed on cell surfaces is capable of interacting with SIRP_ to inhibit phagocytosis. However, ligation of the autogenous, but not cross-dressed, CD47 induced cell death. Thus, CD47 cross-dressing provides an alternative source of cell surface CD47 that may elicit its anti-phagocytic function without transmitting harmful signals to the cells. CD47 cross-dressing also suggests a previously unidentified mechanism for tumor-induced immunosuppression. Our findings should help to further optimize the CD47 transgenic approach that may improve outcomes by minimizing the harmful effects of CD47 overexpression.

Author Info: (1) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China. Colu

Author Info: (1) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (2) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (3) Lung Biotechnology PBC, Silver Spring, United States. (4) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China. (5) Lung Biotechnology PBC, Silver Spring, United States. (6) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (7) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (8) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (9) Lung Biotechnology PBC, Silver Spring, United States. (10) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States. (11) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China. International Center of Future Science, Jilin University, Changchun, China.

Bring on the brequinar: an approach to enforce the differentiation of myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) hinder antitumor immunity in multiple cancer types. While brequinar (BRQ), an inhibitor of dihydroorotate dehydrogenase, shows cytotoxicity in hematological malignancy, it has not yet been adapted to attenuate MDSCs by augmenting bone marrow progenitors in breast cancer. In this issue of the JCI, Colligan et al. demonstrate that BRQ restored terminal differentiation of MDSCs. Using in vivo models of immunotherapy-resistant breast cancer, the authors uncovered a mechanism by which BRQ promoted myeloid cell differentiation by limiting their suppressive function and enhancing the efficacy of immune checkpoint blockade therapy. The findings offer insight into the biogenesis of MDSCs, provide an alternative avenue for cancers that remain unresponsive to conventional therapies, and may be extended to future translational studies in patients.

Author Info: (1) (2)

Author Info: (1) (2)

Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors

Insufficient intratumoral T-cell infiltration and lack of tumor-specific immune surveillance in tumor microenvironment (TME) hinder the progression of cancer immunotherapy. In this study, we explored a recombinant vaccinia virus encoding an EpCAM BiTE (VV-EpCAM BiTE) to modulate the immune suppressive microenvironment to enhance antitumor immunity in several solid tumors. VV-EpCAM BiTE effectively infected, replicated and lysed malignant cells. The EpCAM BiTE secreted from infected malignants effectively mediated the binding of EpCAM-positive tumor cells and CD3_ on T cells, which led to activation of naive T-cell and the release of cytokines, such as IFN-_ and IL-2. Intratumoral administration of VV-EpCAM BiTE significantly enhanced antitumor activity in malignancies with high other than with low EpCAM expression level. In addition, immune cell infiltration was significantly increased in TME upon VV-EpCAM BiTE treatment, CD8(+) T cell exhaustion was reduced and T-cell-mediated immune activation was markedly enhanced. Taken together, VV-EpCAM BiTE sophistically combines the antitumor advantages of bispecific antibodies and oncolytic viruses, which provides preclinical evidence for the therapeutic potential of VV-EpCAM BiTE.

Author Info: (1) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing Unive

Author Info: (1) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. (2) Liuzhou Key Laboratory of Molecular Diagnosis, Guangxi Key Laboratory of Molecular Diagnosis and Application, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi, China. (3) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. (4) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. (5) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. (6) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. (7) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. (8) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. (9) Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.

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