Journal Articles

CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as the absence of cell surface receptors renders it more difficult to be therapeutically targeted. Chemokine receptor 2 (CXCR2) has been suggested not only to promote therapy resistance and suppress immunotherapy but it also to possess a positive cross-talk with the multifunctional cytokine transforming growth factor beta (TGF-_). Here, we showed that CXCR2 and TGF-_ signaling were both upregulated in human TNBC biopsies. CXCR2 inhibition abrogated doxorubicin-mediated TGF-_ upregulation in 3D in vitro TNBC coculture with PBMCs and eliminated drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC doxorubicin-resistance via TGF-_ signaling regulation. Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "atezolizumab" where the combined inhibition of CXCR2 and PDL1 in TNBC in vitro coculture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.

Author Info: (1) The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cair

Author Info: (1) The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt. (2) Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt. (3) The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.

IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer

Although lung cancer is the leading cause of cancer deaths worldwide, the mechanisms how lung cancer cells evade the immune system remain incompletely understood. Here, we discovered IL-9-dependent signaling mechanisms that drive immune evasion in non-small cell lung cancer (NSCLC). We found increased IL-9 and IL-21 production by T cells in the tumoral region of the lung of patients with NSCLC, suggesting the presence of Th9 cells in the lung tumor microenvironment. Moreover, we noted IL-9 producing Tregs in NSCLC. IL-9 target cells in NSCLC consisted of IL-9R+ tumor cells and tumor-infiltrating lymphocytes. In two murine experimental models of NSCLC, and in vitro, IL-9 prevented cell death and controlled growth of lung adenocarcinoma cells. Targeted deletion of IL-9 resulted in successful lung tumor rejection in vivo associated with an induction of IL-21 and reduction of Treg cells. Finally, anti-IL-9 antibody immunotherapy resulted in suppression of tumor development even in established experimental NSCLC and was associated with reduced IL-10 production in the lung. In conclusion, our findings indicate that IL-9 drives immune escape of lung tumor cells via effects on tumor cell survival and tumor infiltrating T cells. Thus, strategies blocking IL-9 emerge as a new approach for clinical therapy of lung cancer.

Author Info: (1) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (2) Department of Molecular Pneumology, Friedrich-Alexander-Univ

Author Info: (1) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (2) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (3) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (4) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (5) Department of Internal Medicine 1, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (6) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (7) Institute of Pathology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (8) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (9) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (10) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (11) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (12) Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States. (13) Institute of Pathology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (14) Department of Thoracic Surgery, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (15) Department of Thoracic Surgery, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (16) Department of Internal Medicine 1, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (17) Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States. (18) Department of Molecular Pneumology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany.

Integrative lymph node-mimicking models created with biomaterials and computational tools to study the immune system

The lymph node (LN) is a vital organ of the lymphatic and immune system that enables timely detection, response, and clearance of harmful substances from the body. Each LN comprises of distinct substructures, which host a plethora of immune cell types working in tandem to coordinate complex innate and adaptive immune responses. An improved understanding of LN biology could facilitate treatment in LN-associated pathologies and immunotherapeutic interventions, yet at present, animal models, which often have poor physiological relevance, are the most popular experimental platforms. Emerging biomaterial engineering offers powerful alternatives, with the potential to circumvent limitations of animal models, for in-depth characterization and engineering of the lymphatic and adaptive immune system. In addition, mathematical and computational approaches, particularly in the current age of big data research, are reliable tools to verify and complement biomaterial works. In this review, we first discuss the importance of lymph node in immunity protection followed by recent advances using biomaterials to create in vitro/vivo LN-mimicking models to recreate the lymphoid tissue microstructure and microenvironment, as well as to describe the related immuno-functionality for biological investigation. We also explore the great potential of mathematical and computational models to serve as in silico supports. Furthermore, we suggest how both in vitro/vivo and in silico approaches can be integrated to strengthen basic patho-biological research, translational drug screening and clinical personalized therapies. We hope that this review will promote synergistic collaborations to accelerate progress of LN-mimicking systems to enhance understanding of immuno-complexity.

Author Info: (1) Department of Biomedical Engineering, National University of Singapore, 117583, Singapore. (2) Department of Bioengineering, Stanford University, CA, 94305, USA. Department of

Author Info: (1) Department of Biomedical Engineering, National University of Singapore, 117583, Singapore. (2) Department of Bioengineering, Stanford University, CA, 94305, USA. Department of Bioengineering, Imperial College London, South Kensington, SW72AZ, UK. (3) Department of Biomedical Engineering, National University of Singapore, 117583, Singapore. Singapore Immunology Network, Agency for Science, Technology and Research, 138648, Singapore. (4) Department of Biomedical Engineering, National University of Singapore, 117583, Singapore. (5) Department of Biomedical Engineering, National University of Singapore, 117583, Singapore. Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore. NUS Tissue Engineering Program, National University of Singapore, 117510, Singapore.

Reversal of the T cell immune system reveals the molecular basis for T cell lineage fate determination in the thymus

T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8-regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.

Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Viral Immunology and Intravital Imaging Section, National Insti

Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Department of Immunology, Duke University School of Medicine, Durham, NC, USA. (3) Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. (4) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (7) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (8) Office of Science and Technology Resources, Office of the Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. CCR-SF Bioinformatics Group, Advanced Biomedical Computational Science, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. (9) Office of Science and Technology Resources, Office of the Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (10) Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. (11) Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey. (12) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Singera@nih.gov.

Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model

Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including _-galactosylceramide, _GC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether _GC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with _GC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at_~_20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by_~_40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFN_ in response to tumor cells. The vaccine was not effective if the _GC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation.

Author Info: (1) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Sana Biotechnology Inc., Boston, MA, USA. (2) Beth Israel Deaconess

Author Info: (1) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Sana Biotechnology Inc., Boston, MA, USA. (2) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Brigham and Women's Hospital, 75 Francis St., NRB 6, Boston, MA, 02115, USA. (3) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. (4) Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Sanofi Inc., San Diego, CA, USA. (5) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. (6) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Emory University, Atlanta, GA, USA. (7) Medical Center School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA. (8) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Emory University, Atlanta, GA, USA. (9) Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Novartis Biomedical Institutes of Research, Cambridge, MA, USA. (10) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. Intellia Inc., Cambridge, MA, USA. (11) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. sbalk@bidmc.harvard.edu. (12) Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. mexley@partners.org. Brigham and Women's Hospital, 75 Francis St., NRB 6, Boston, MA, 02115, USA. mexley@partners.org. Imvax Inc., Philadelphia, PA, USA. mexley@partners.org. University of Manchester, Manchester, UK. mexley@partners.org. MiNK Therapeutics Inc., New York, NY, USA. mexley@partners.org.

The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy

Immune checkpoint molecules play critical roles in regulating the anti-tumor immune response, and tumor cells often exploit these pathways to inhibit and evade the immune system. The B7-family immune checkpoint B7x is widely expressed in a broad variety of cancer types, and is generally associated with advanced disease progression and poorer clinical outcomes, but the underlying mechanisms are unclear. Here, we show that transduction and stable expression of B7x in multiple syngeneic tumor models leads to the expansion of immunosuppressive regulatory T cells (Tregs). Mechanistically, B7x does not cause increased proliferation of Tregs in tumors, but instead promotes the conversion of conventional CD4(+) T cells into Tregs. Further, we find that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. B7x increases the expression of the Treg-specific transcription factor Foxp3 in CD4(+) T cells by modulating the Akt/Foxo pathway. B7x-mediated regulation of Tregs reduces the efficacy of anti-CTLA-4 treatment, a therapeutic that partially relies on Treg-depletion. However, combination treatment of anti-B7x and anti-CTLA-4 leads to synergistic therapeutic efficacy and overcomes the B7x-mediated resistance to anti-CTLA-4. Altogether, B7x mediates an immunosuppressive Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.

Author Info: (1) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. (2) Department of Microbiology & Immunology, Albert Einstein College of

Author Info: (1) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. (2) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. (3) Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. (4) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. (5) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. (6) Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States. (7) Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States. xingxing.zang@einsteinmed.edu. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States. xingxing.zang@einsteinmed.edu. Department of Urology, Albert Einstein College of Medicine, Bronx, NY, United States. xingxing.zang@einsteinmed.edu.

Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4(+) T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4(+) T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.

Author Info: (1) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentru

Author Info: (1) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (2) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (3) Evergrande Center for Immunologic Diseases, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston, MA, USA; Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. (5) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (6) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (7) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (8) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (9) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (10) Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany. (11) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (12) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany. (13) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany. (14) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany. (15) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (16) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (17) Evergrande Center for Immunologic Diseases, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Inflammatory Stress in Stem Cells, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. (19) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (20) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (21) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Inflammatory Stress in Stem Cells, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. (22) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. (23) Research Group GMP & T Cell Therapy, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. (24) Research Group GMP & T Cell Therapy, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. (25) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Inflammatory Stress in Stem Cells, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. (26) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (27) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany. (28) Medical Faculty, University Hospital Carl Gustav Carus, NCT/UCC Section Medical Systems Biology, TU Dresden, Dresden, Germany. (29) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Experimental Hematology, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. (30) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Inflammatory Stress in Stem Cells, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. (31) Research Group GMP & T Cell Therapy, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. (32) Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. (33) Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. (34) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Computational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg and Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. (35) Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany. (36) German Cancer Consortium (DKTK), Heidelberg, Germany; Medical Department 1, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. (37) German Cancer Consortium (DKTK), Heidelberg, Germany; CharitŽ-UniversitŠtsmedizin Berlin, Corporate Member of Freie UniversitŠt Berlin, Humboldt-UniversitŠt zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany. (38) Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany. (39) Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston, MA, USA; Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. (40) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: a.trumpp@dkfz.de. (41) Evergrande Center for Immunologic Diseases, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu. (42) Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; CharitŽ-UniversitŠtsmedizin Berlin, Corporate Member of Freie UniversitŠt Berlin, Humboldt-UniversitŠt zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany; Berlin Institute of Health (BIH) at CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany; Berlin Institute for Medical Systems Biology, Max DelbrŸck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. Electronic address: simon.haas@bih-charite.de.

Rational Design and Systemic Appraisal of an EGFR-Targeting Antibody-Drug Conjugate LR-DM1 for Pancreatic Cancer

By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity in vitro with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition in vivo under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.

Author Info: (1) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (2) Institute of Medicinal Biotechnology, Chin

Author Info: (1) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (2) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (3) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (4) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (5) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (6) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (7) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (8) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (9) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (10) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. (11) Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.

Inflammasomes in Cancer Progression and Anti-Tumor Immunity

The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1_ and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.

Author Info: (1) CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France. (2) CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France. > Adjunct Professor, Depar

Author Info: (1) CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France. (2) CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France. > Adjunct Professor, Department of Medicine, McGill University, Montreal, QC, Canada.

Injectable Hydrogel Containing Cowpea Mosaic Virus Nanoparticles Prevents Colon Cancer Growth

Despite advances in laparoscopic surgery combined with neoadjuvant and adjuvant therapy, colon cancer management remains challenging in oncology. Recurrence of cancerous tissue locally or in distant organs (metastasis) is the major problem in colon cancer management. Vaccines and immunotherapies hold promise in preventing cancer recurrence through stimulation of the immune system. We and others have shown that nanoparticles from plant viruses, such as cowpea mosaic virus (CPMV) nanoparticles, are potent immune adjuvants for cancer vaccines and serve as immunostimulatory agents in the treatment or prevention of tumors. While being noninfectious toward mammals, CPMV activates the innate immune system through recognition by pattern recognition receptors (PRRs). While the particulate structure of CPMV is essential for prominent immune activation, the proteinaceous architecture makes CPMV subject to degradation in vivo; thus, CPMV immunotherapy requires repeated injections for optimal outcome. Frequent intraperitoneal (IP) injections however are not optimal from a clinical point of view and can worsen the patient's quality of life due to the hospitalization required for IP administration. To overcome the need for repeated IP injections, we loaded CPMV nanoparticles in injectable chitosan/glycerophosphate (GP) hydrogel formulations, characterized their slow-release potential, and assessed the antitumor preventative efficacy of CPMV-in-hydrogel single dose versus soluble CPMV (single and prime-boost administration). Using fluorescently labeled CPMV-in-hydrogel formulations, in vivo release data indicated that single IP injection of the hydrogel formulation yielded a gel depot that supplied intact CPMV over the study period of 3 weeks, while soluble CPMV lasted only for one week. IP administration of the CPMV-in-hydrogel formulation boosted with soluble CPMV for combined immediate and sustained immune activation significantly inhibited colon cancer growth after CT26 IP challenge in BALB/c mice. The observed antitumor efficacy suggests that CPMV can be formulated in a chitosan/GP hydrogel to achieve prolonged immunostimulatory effects as single-dose immunotherapy against colon cancer recurrence. The present findings illustrate the potential of injectable hydrogel technology to accommodate plant virus nanoparticles to boost the translational development of effective antitumor immunotherapies.

Author Info: (1) (2)

Author Info: (1) (2)

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