Journal Articles

Tumor-Derived Small Extracellular Vesicles Induce Pro-Inflammatory Cytokine Expression and PD-L1 Regulation in M0 Macrophages via IL-6/STAT3 and TLR4 Signaling Pathways

Tumor-associated macrophages play a key role in promoting tumor progression by exerting an immunosuppressive phenotype associated with the expression of programmed cell death ligand 1 (PD-L1). It is well known that tumor-derived small extracellular vesicles (SEVs) affect the tumor microenvironment, influencing TAM behavior. The present study aimed to examine the effect of SEVs derived from colon cancer and multiple myeloma cells on macrophage functions. Non-polarized macrophages (M0) differentiated from THP-1 cells were co-cultured with SEVs derived from a colorectal cancer (CRC) cell line, SW480, and a multiple myeloma (MM) cell line, MM1.S. The expression of PD-L1, interleukin-6 (IL-6), and other inflammatory cytokines as well as of the underlying molecular mechanisms were evaluated. Our results indicate that SEVs can significantly upregulate the expressions of PD-L1 and IL-6 at both the mRNA and protein levels and can activate the STAT3 signaling pathway. Furthermore, we identified the TLR4/NF-kB pathway as a convergent mechanism for SEV-mediated PD-L1 expression. Overall, these preliminary data suggest that SEVs contribute to the formation of an immunosuppressive microenvironment.

Author Info: (1) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (2) Department of Biomedicine, Neuroscience and Advanced

Author Info: (1) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (2) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (3) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (4) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (5) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (6) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (7) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. Central Laboratory of Advanced Diagnosis and Biomedical Research, 90133 Palermo, Italy. (8) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. Central Laboratory of Advanced Diagnosis and Biomedical Research, 90133 Palermo, Italy. (9) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. (10) Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, 90133 Palermo, Italy. Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy.

Two Faces of Macrophages: Training and Tolerance

Macrophages are present in almost all body tissues. They detect and quickly respond to "environmental signals" in the tissue. Macrophages have been associated with numerous beneficial roles, such as host defense, wound healing, and tissue regeneration; however, they have also been linked to the development of diverse illnesses, particularly cancers and autoimmune disorders. Complex signaling, epigenetic, and metabolic pathways drive macrophage training and tolerance. The induced intracellular program differs depending on the type of initial stimuli and the tissue microenvironment. Due to the essential roles of macrophages in homeostatic and their association with the pathogenesis of inflammatory diseases, recent studies have investigated the molecular mechanisms of macrophage training and tolerance. This review discusses the role of factors involved in macrophage training and tolerance, along with the current studies in human diseases.

Author Info: (1) Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Korea. (2) Department of Biological Sciences and Biotechnology, Chungbuk Nati

Author Info: (1) Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Korea. (2) Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Korea. (3) Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Korea. (4) Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Korea.

Highlights of Immunomodulation in Salmonella-Based Cancer Therapy

Bacteria-mediated cancer therapy (BMCT) is an emerging tool that may advance potential approaches in cancer immunotherapy, whereby tumors are eradicated by the hosts' immune system upon recruitment and activation by bacteria such as Salmonella. This paper provides an emphasis on the immunomodulatory effects that encompasses both the innate and adaptive immune responses inherently triggered by Salmonella. Furthermore, modifications of Salmonella-based treatment in the attempt to improve tumor-specific immune responses including cytokine therapy, gene therapy, and DNA vaccine delivery are likewise discussed. The majority of the findings described herein incorporate cell-based experiments and murine model studies, and only a few accounts describe clinical trials. Salmonella-based cancer therapy is still under development; nonetheless, the pre-clinical research and early-phase clinical trials that have been completed so far have shown promising and convincing results. Certainly, the continuous development of, and innovation on, Salmonella-based therapy could pave the way for its eventual emergence as one of the mainstream therapeutic interventions addressing various types of cancer.

Author Info: (1) Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. (2) Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 8

Author Info: (1) Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. (2) Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan. Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. International PhD Program for Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.

CSMD1 Mutations Are Associated with Increased Mutational Burden, Favorable Prognosis, and Anti-Tumor Immunity in Gastric Cancer

Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). To find specific gene mutations related to TMB and the prognosis of patients, the frequently mutated genes in gastric cancer patients from TCGA and ICGC were obtained and the correlation between gene mutation, TMB, and prognosis was analyzed. Furthermore, to clarify whether specific gene mutations can be used as predictive biomarkers of ICIs, a gene set enrichment analysis (GSEA) for immune pathways and an immune infiltration analysis were conducted. The results showed that CUB and Sushi multiple domains 1 (CSMD1) mutation (CSMD1-mut) were associated with higher TMB and better prognosis in patients. The genetic map showed that, compared with wild-type samples, the loss of chromosomes 4q, 5q, 8p, and 9p decreased and the status of microsatellite instability increased in the CSMD1-mut samples. The GSEA analysis showed that immune-related pathways were enriched in the CSMD1-mut samples. The immune infiltration analysis showed that the anti-tumor immune cells were upregulated and that the tumor-promoting immune cells were downregulated in the CSMD1-mut samples. The gene co-expression analysis showed that PD-L1 expression was higher in the CSMD1-mut samples. In summary, CSMD1-mut in gastric cancer was associated with increased TMB and favorable survival and may have potential significance in predicting the efficacy of anti-PD-L1.

Author Info: (1) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China.

Author Info: (1) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China. (2) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China. (3) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China. (4) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China. (5) The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China. (6) Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou 730000, China. (7) Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China.

Cancer Immunotherapy: Current and Future Perspectives on a Therapeutic Revolution

The advent of immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors [...].

Author Info: (1) Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15, 40121 Bologna, Italy. (2) Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di B

Author Info: (1) Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15, 40121 Bologna, Italy. (2) Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15, 40121 Bologna, Italy. (3) Medical Oncology Unit, Macerata General Hospital, 62100 Macerata, Italy. (4) Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15, 40121 Bologna, Italy.

There Is Strength in Numbers: Quantitation of Fc Gamma Receptors on Murine Tissue-Resident Macrophages

Many of the effector functions of antibodies rely on the binding of antibodies/immune complexes to cellular Fc_ receptors (Fc_Rs). Since the majority of innate immune effector cells express both activating and inhibitory Fc receptors, the outcome of the binding of immune complexes to cells of a given population is influenced by the relative affinities of the respective IgG subclasses to these receptors, as well as by the numbers of activating and inhibitory Fc_Rs on the cell surface. A group of immune cells that has come into focus more recently is the various subsets of tissue-resident macrophages. The central functions of Fc_Rs on tissue macrophages include the clearance of opsonized pathogens, the removal of small immune complexes from the circulation and the depletion of antibody-opsonized cells in the therapy of autoimmunity and cancer. Despite these essential functions of Fc_Rs on tissue-resident macrophages, an in-depth quantification of Fc_Rs is lacking. Thus, the aim of our current study was to quantify the various Fc_ receptors on macrophages in murine liver, lung, kidney, brain, skin and spleen. Our study identified a pronounced heterogeneity between Fc_R expression patterns of the different tissue macrophages, which may reflect their specialized functions within their unique niches in different organ environments.

Author Info: (1) Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-NŸrnberg, 91058 Erlangen, Germany. (2) Division of Genetics, Department of Biology, Friedri

Author Info: (1) Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-NŸrnberg, 91058 Erlangen, Germany. (2) Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-NŸrnberg, 91058 Erlangen, Germany. (3) Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-NŸrnberg, 91058 Erlangen, Germany. Medical Immunology Campus Erlangen, Friedrich-Alexander University Erlangen-NŸrnberg, 91052 Erlangen, Germany. (4) Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-NŸrnberg, 91058 Erlangen, Germany. Medical Immunology Campus Erlangen, Friedrich-Alexander University Erlangen-NŸrnberg, 91052 Erlangen, Germany.

Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Due to their expression pattern, they have historically been attractive targets for immunotherapies. A growing number of studies implicate CT antigens in almost all hallmarks of cancer, suggesting that they may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas. However, their role in the pathogenesis of these cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.

Author Info: (1) Molecular Microbiology Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA. (2) Department of Developmental, Molecular,

Author Info: (1) Molecular Microbiology Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA. (2) Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.

Cancer Immunology and Immunotherapies: Mechanisms That Affect Antitumor Immune Response and Treatment Resistance

The past decade has seen immunotherapy rise to the forefront of cancer treatment [...].

Author Info: (1) Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55

Author Info: (1) Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.

Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate na•ve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

Author Info: (1) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. Pharos Vaccine Inc., 14 Galmachiro 288 bun-gil, Jungwon-gu, Seongnam

Author Info: (1) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. Pharos Vaccine Inc., 14 Galmachiro 288 bun-gil, Jungwon-gu, Seongnam 13201, Gyeonggi-do, Korea. (2) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (3) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (4) Pharos Vaccine Inc., 14 Galmachiro 288 bun-gil, Jungwon-gu, Seongnam 13201, Gyeonggi-do, Korea. (5) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (6) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (7) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (8) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (9) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (10) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea. (11) Department of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea. (12) Department of Food Science and Biotechnology of Animal Products, Sanghuh College of Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea. (13) Department of Biotechnology, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, Gyeonggi-do, Korea.

Overweight as a Favorable Clinical Biomarker for Checkpoint Inhibitor Therapy Response in Recurrent Gynecologic Cancer Patients

Despite increasing clinical interest in adapting checkpoint inhibitor (CPI) therapies for patients with gynecologic malignancies, no accurate clinical biomarkers to predict therapy response and prognosis are currently available. Therefore, we aimed to assess the predictive and prognostic value of pretherapeutic body mass index (BMI) for recurrent gynecologic cancer patients as previously validated for other solid tumors. We evaluated patients with programmed cell death ligand 1 (PD-L1) positive and, in endometrial cancer, also mismatch repair deficient (MMR) gynecologic malignancies, who received the PD-1 inhibitor pembrolizumab as monotherapy (200 mg fixed-dose q3 w) from 2017 to 2020 (n = 48). Thirty-six patients receiving at least four courses were included in the final analysis. Associations between a BMI increase per 5 kg/m(2) and overall response rate (ORR; complete + partial response), disease control rate (DCR; ORR + stable disease), progression-free (PFS), and overall survival (OS) were assessed. An elevated BMI was univariately associated with ORR (OR 10.93 [CI 2.39-49.82], p = 0.002), DCR (OR 2.19 [CI 0.99-4.83], p = 0.048), prolonged PFS (HR 1.54 [CI 1.03-2.34], p = 0.038), and OS (HR 1.87 [CI 1.07-3.29], p = 0.028). All results could be confirmed in the multivariate analyses. Pretherapeutic BMI therefore appears to be a promising readily available biomarker to identify patients with PD-L1-positive and/or MMR-deficient gynecologic malignancies who could particularly benefit from CPI treatment.

Author Info: (1) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria. (2) Department of Obstetri

Author Info: (1) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria. (2) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria. (3) Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria. (4) Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria. (5) Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria. (6) Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria. (7) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria. (8) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria. Karl Landsteiner Institute for General Gynecology and Experimental Gynecologic Oncology, Karl Landsteiner Society, 3100 St. Poelten, Austria. (9) Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria.

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