Journal Articles

Immune suppression

Local and peripheral suppression of immune cell activity, immune escape and strategies to revert these pro-tumorigenic mechanisms; cell types with immunosuppressive function

M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas

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BACKGROUND: Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis. METHODS: Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data. RESULTS: TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively. CONCLUSION: M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma.

Author Info: (1) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (2) Medical Research Collaborating Center, Seoul National

Author Info: (1) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (2) Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea. (3) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (4) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (5) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (6) Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. (7) Department of Pathology, Yonsei University, College of Medicine, Severance Hospital, Seoul, Republic of Korea. (8) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea. (9) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. phi.jihoon@gmail.com.

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CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T Cell Hypofunction

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One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment, which inactivates the function of tumor infiltrating lymphocytes (TILs) through the production of immunosuppressive molecules such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the tumor microenvironment (TME). To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLVs) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME.

Author Info: (1) Chemical Engineering and Materials Science, University of Southern California. (2) Pharmacology and Pharmaceutical Sciences, University of Southern California. (3) Biomedical Engineering, University of Southern

Author Info: (1) Chemical Engineering and Materials Science, University of Southern California. (2) Pharmacology and Pharmaceutical Sciences, University of Southern California. (3) Biomedical Engineering, University of Southern California. (4) Pharmacology and Pharmaceutical Sciences, University of Southern California. (5) Biomedical Engineering, University of Southern California. (6) R&D, HRAIN Biotechnology Co. Ltd. (7) Chemical Engineering and Materials Science, University of Southern California pinwang@usc.edu.

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Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome

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Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161(+) CD4(+) and CD8(+) T cells as compared to normal distant lung and peripheral blood. CD161(+) CD4(+) T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161(+) CD4(+) T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4(+) T cells ideal candidates for efficient anti-tumor recall responses.

Author Info: (1) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (2) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy"

Author Info: (1) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (2) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (3) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (4) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (5) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Pathology, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (6) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (7) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Pathology, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (8) University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Thoracic Surgery, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (9) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. Department of Pathology, Institut Mutualiste Montsouris, Paris, France. (10) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (11) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (12) University of Lyon, University Lyon 1, Lyon, France. Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France. (13) Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France. (14) Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France. Paris 13 University, Sorbonne Paris Cite, Faculty of Medicine SMBH, Bobigny, France. (15) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (16) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France.

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Targeted overexpression of prostacyclin synthase inhibits lung tumor progression by recruiting CD4+ T lymphocytes in tumors that express MHC class II

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Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We investigated the effects of pulmonary PGIS overexpression in an orthotopic immunocompetent mouse model of lung cancer using two murine lung cancer cell lines. Pulmonary PGIS overexpression significantly inhibited CMT167 lung tumor growth, increased CXCL9 expression, and increased CD4+ tumor-infiltrating lymphocytes. Immunodepletion of CD4+ T cells abolished the inhibitory effect of pulmonary PGIS overexpression on CMT167 lung tumor growth. In contrast, pulmonary PGIS overexpression failed to inhibit growth of a second murine lung cancer cell line, Lewis Lung Carcinoma (LLC) cells, and failed to increase CXCL9 expression or CD4+ T lymphocytes in LLC lung tumors. Transcriptome profiling of CMT167 cells and LLC cells recovered from tumor-bearing mice demonstrated that in vivo, CMT167 cells but not LLC cells express MHC class II genes and cofactors necessary for MHC class II processing and presentation. These data demonstrate that prostacyclin can inhibit lung cancer progression and suggest that prostacyclin analogs may serve as novel immunomodulatory agents in a subset of lung cancer patients. Moreover, expression of MHC Class II by lung cancer cells may represent a biomarker for response to prostacyclin.

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (4) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (5) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (6) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (7) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (8) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (9) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (10) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (11) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (12) Departments of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (13) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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PD-L1 expression in medulloblastoma: an evaluation by subgroup

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Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-gamma robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-gamma), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (3) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (4) Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA. (5) Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA. (6) Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA. (7) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA. (8) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (9) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (10) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (11) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (12) In Jackson, MS, USA. (13) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (14) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (15) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (16) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (17) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (18) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (19) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (20) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (21) Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA. (22) Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA.

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CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma

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CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine whether exogenous exposure to CD200fc mimics the effects of endogenously over expressed CD200. Female BALB/c mice were injected with CD200fc two times a week for five times. Injection was started two days after orthotopic injection of 4THM cells. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection significantly decreased lung and liver metastasis and the growth of primary tumors. CD200fc injection enhanced the tumor-induced IFN-g response while suppressing the IL-10 response. We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells. These results are in accord with previous data from CD200 transgenic mice, and demonstrate for the first time that CD200 analogues might have therapeutic potential in the treatment of aggressive breast carcinoma which induces excessive systemic inflammation.

Author Info: (1) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (2) Histology and Embryology, Akdeniz University, School of Medicine, Antalya, Turkey. (3) University

Author Info: (1) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (2) Histology and Embryology, Akdeniz University, School of Medicine, Antalya, Turkey. (3) University Health Network, Toronto General Hospital, Toronto, Canada. (4) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (5) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (6) University Health Network, Toronto General Hospital, Toronto, Canada.

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Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs

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Therapeutic role of NK cells in solid tumors was challenged previously even though their role in hematological malignancies has clearly been established. Furthermore, functions and numbers of NK cells are greatly suppressed in oral cancer patients necessitating effective future NK immunotherapeutic strategies to aid in the control of disease. The humanized-BLT (hu-BLT) mice were used to implant stem-like/undifferentiated oral tumors to study the role of super-charged NK cells with and without feeding with AJ2 probiotic bacteria. Implanted CSC/undifferentiated tumors resected from NK-injected mice exhibited differentiated phenotype, grew slowly, and did not cause weight loss, whereas those from tumor-bearing mice without NK-injection remained relatively more stem-like/poorly-differentiated, grew faster, and caused significant weight loss. Moreover, in vitro NK-differentiated tumors were sensitive to chemotherapeutic drugs, and when implanted in the oral-cavity grew no or very small tumors in mice. When NK-mediated differentiation of tumors was blocked by IFN-gamma and TNF-alpha antibodies before implantation, tumors grew rapidly, remained stem-like/poorly-differentiated and became resistant to chemotherapeutic drugs. Loss of NK cytotoxicity and decreased IFN-gamma secretion in tumor-bearing mice in PBMCs, splenocytes, bone marrow derived immune cells and enriched NK cells was restored by the injection of super-charged NK cells with or without feeding with AJ2. Much greater infiltration of CD45(+) and T cells were observed in tumors resected from the mice, along with the restored secretion of IFN-gamma from purified T cells from splenocytes in NK-injected tumor-bearing mice fed with AJ2 probiotic bacteria. Thus, super-charged NK cells prevent tumor growth by restoring effector function resulting in differentiation of CSCs/undifferentiated-tumors in hu-BLT mice.

Author Info: (1) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (2) Division of Oral

Author Info: (1) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (2) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (3) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland. (4) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (5) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (6) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (7) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (8) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. (9) Pingan Advanced Personalized Diagnostics, Biomed Co. (USA and Beijing), Beijing, China. (10) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, CA, USA. (11) Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA.

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Myeloid-derived macrophages and secreted HSP90alpha induce pancreatic ductal adenocarcinoma development

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We detected a significant elevation of serum HSP90alpha levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90alpha levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90alpha levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90alpha levels were detected before PDAC formation and an extracellular HSP90alpha (eHSP90alpha) inhibitor effectively prevented PDAC development. Both serum HSP90alpha level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b(+)-myeloid cells were associated with eHSP90alpha levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b(+)-myeloid cells depletion, serum HSP90alpha levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue-infiltrating CD11b(+)-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90alpha-expressing CD11b(+)-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90alpha-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90alpha could be produced by macrophages and macrophage-stimulated PDE cells. Macrophages not only secreted significant amount of HSP90alpha, but also secreted interleukin-6 and interleukin-8 to induce a JAK2-STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90alpha. eHSP90alpha further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90alpha can be potentially taken as a target to suppress PDAC pathogenesis.

Author Info: (1) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (2) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (3)

Author Info: (1) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (2) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (3) Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei, Taiwan. (4) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (5) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (6) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (7) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (8) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (9) Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei, Taiwan. (10) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (11) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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LW106, A Novel Inhibitor of IDO1, Suppresses Tumor Progression by Limiting Stroma-Immune Crosstalk and Cancer Stem Cell Enrichment in the Tumor Microenvironment

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BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumor effects and the underlying mechanisms in two Tumor models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1(-/-) mice were inoculated with IDO1-expressing and -nonexpressing tumor cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted Tumors, plasmas, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose-dependently inhibited outgrowth of xenografted tumors that were inoculated in C57BL6 mice but not nude mice or Ido1(-/-) mice, showing a stronger antitumor efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoral infiltration of proliferative Teff cells while reduced recruitment of proliferative Treg cells and non-hematopoietic stromal cells such as endothelial cells and cancer-associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumors in which less proliferative/invasive tumor cells and more apoptotic tumor cells were observed. CONCLUSION AND IMPLICATIONS: LW106 inhibits tumor outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumor microenvironment. LW106 can be further developed as a potential immunotherapeutic agent used in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.

Author Info: (1) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing

Author Info: (1) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. (2) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. (3) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China. (4) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. (5) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. (6) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Collaborative Innovation Center for Gannan Oil-Tea Camellia Industrial Development, Gannan Medical University, Ganzhou, 341000, China. (7) Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China. (8) The Life Sciences Institute, Comprehensive Cancer Center, Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA. (9) Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. (10) State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.

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Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages towards tumor-suppressing phenotype

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Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In this study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2, and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. (2) Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. (3) Department of

Author Info: (1) Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. (2) Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. (3) Department of Microbiology and Immunology, National Cheng Kung University, Tainan 70101, Taiwan. (4) Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University, Tainan 70101, Taiwan. (5) Division of Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. (6) Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

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