Journal Articles

Cancer Immunobiology

Basic research studies that extend knowledge in the field of cancer immunotherapy

The Urinary Microbiome: Implications in Bladder Cancer Pathogenesis and Therapeutics

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Recent investigation has proven that the bladder is not sterile. However, the implications of this finding in the pathophysiology and management of urothelial cell carcinoma have not been fully described. In this review, we summarize the literature relating to the urinary and gastrointestinal microbiomes in the context of urothelial cell carcinoma. The bladder microbiome may relate to urothelial cell carcinoma pathogenesis/progression, act as a non-invasive and modifiable urinary biomarker and have implications in treatment using immunotherapy agents such as intravesical Bacillus Calmette Guerin. Investigators should continue to optimize techniques to characterize this intriguing new area of human health.

Author Info: (1) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: pbajic@lumc.edu. (2) Department of Microbiology and Immunology, Stritch School

Author Info: (1) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: pbajic@lumc.edu. (2) Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: awolfe@luc.edu. (3) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: gogupta@lumc.edu.

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Natural modulators of the hallmarks of immunogenic cell death

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Natural compounds act as immunoadjuvants as their therapeutic effects trigger cancer stress response and release of damage-associated molecular patterns (DAMPs). These reactions occur through an increase in the immunogenicity of cancer cells that undergo stress followed by immunogenic cell death (ICD). These processes result in a chemotherapeutic response with a potent immune-mediating reaction. Natural compounds that induce ICD may function as an interesting approach in converting cancer into its own vaccine. However, multiple parameters determine whether a compound can act as an ICD inducer, including the nature of the inducer, the premortem stress pathways, the cell death pathways, the intrinsic antigenicity of the cell, and the potency and availability of an immune cell response. Thus, the identification of hallmarks of ICD is important in determining the prognostic biomarkers for new therapeutic approaches and combination treatments.

Author Info: (1) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (2) Laboratoire de Biologie Moleculaire et Cellulaire

Author Info: (1) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (2) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (3) College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.

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Endoplasmic Reticulum Stress Responses in Intratumoral Immune Cells: Implications for Cancer Immunotherapy

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Protective anti-tumor immune responses are mediated by effector molecules that enable successful elimination of malignant cells. As the site where transmembrane and secreted proteins are generated, the endoplasmic reticulum (ER) of immune cells plays a key role in this process. Recent studies have indicated that adverse conditions within tumors perturb ER homeostasis in infiltrating immune cells, which can impede the development of effective anti-cancer immunity. Here, we describe how the tumor microenvironment induces ER stress in immune cells, and discuss the detrimental consequences of persistent ER stress responses in intratumoral immune populations. We also explore the concept of targeting ER stress responses to reinvigorate endogenous anti-tumor immunity and enhance the efficacy of various forms of cancer immunotherapy.

Author Info: (1) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York

Author Info: (1) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. (2) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: jur2016@med.cornell.edu.

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Follicular regulatory T cells infiltrated the ovarian carcinoma and resulted in CD8 T cell dysfunction dependent on IL-10 pathway

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A high Treg/CD8 T cell ratio in ovarian carcinoma was negatively associated with the prognosis of the patients. The human follicular regulatory T (Tfr) cells are a newly characterized subset of Treg cells with features of both follicular helper T (Tfh) cells (CXCR5(+)) and canonical Treg cells (CD25(+)Foxp3(+)). The role of Tfr cells in ovarian cancer is yet unclear. We found that in peripheral blood, the ovarian cancer patients presented significantly higher levels of both CD4(+)CD25(+)CD127(-)CXCR5(+) T cells and CD4(+)CD25(+)CD127(-)CXCR5(+)Foxp3(+) T cells than the healthy controls. In resected tumor samples, Tfr cells represented a much greater percentage of lymphocytes than in peripheral blood. Interestingly, the circulating Tfr cells from ovarian cancer patients presented significantly higher TGFB1 and IL10 expression than their counterparts in healthy controls directly ex vivo, and significantly higher IL10 after stimulation. The tumor-infiltrating Tfr cells presented further upregulated expression of TGFB1 and IL10. In addition, the levels of TGFB1 and IL10 expression by Tfr cells negatively associated with the expression of IFNG in tumor-infiltrating CD8 T cells. In an in vitro CD8 T cell/Tfr cell coculture system, we found that Tfr cells could significantly suppress the activation of CD8 T cells, in a manner that was dependent on IL-10 and probably on TGF-beta. Overall, our study found that Tfr cells could suppress CD8 T cells, and in ovarian cancer patients, the Tfr cells were increased in both frequency and function.

Author Info: (1) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. Electronic address: lili_ulmq@sina.com. (2) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical

Author Info: (1) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. Electronic address: lili_ulmq@sina.com. (2) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. (3) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China.

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Recent advances in radiation therapy of pancreatic cancer

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Pancreatic cancer has a dismal prognosis with an overall survival outcome of just 5% at five years. However, paralleling our improved understanding of the biology of pancreatic cancer, treatment paradigms have also continued to evolve with newer advances in surgical techniques, chemotherapeutic agents, radiation therapy (RT) techniques, and immunotherapy paradigms. RT dose, modality, fraction size, and sequencing are being evaluated actively, and the interplay between RT and immune effects has opened up newer avenues of research. In this review, we will emphasize recent advances in RT for pancreatic cancer, focusing on preoperative chemoradiation, RT dose escalation, sparing of the spleen to reduce lymphopenia, and combination of RT with immunotherapy.

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

Author Info: (1) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. The University of Texas MD Anderson Cancer Center-UT Health Graduate School of Biomedical Sciences, Houston, TX, USA. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and Chang Gung University, Taoyuan, Taiwan. (3) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. The University of Texas MD Anderson Cancer Center-UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.

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Arg1 expression defines immunosuppressive subsets of tumor-associated macrophages

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Tumor-associated macrophages (TAM) have attracted attention as they can modulate key cancer-related activities, yet TAM represent a heterogenous group of cells that remain incompletely characterized. In growing tumors, TAM are often referred to as M2-like macrophages, which are cells that display immunosuppressive and tumorigenic functions and express the enzyme arginase 1 (Arg1). Methods: Here we combined high resolution intravital imaging with single cell RNA seq to uncover the topography and molecular profiles of immunosuppressive macrophages in mice. We further assessed how immunotherapeutic interventions impact these cells directly in vivo. Results: We show that: i) Arg1+ macrophages are more abundant in tumors compared to other organs; ii) there exist two morphologically distinct subsets of Arg1 TAM defined by previously unknown markers (Gbp2b, Bst1, Sgk1, Pmepa1, Ms4a7); iii) anti-Programmed Cell Death-1 (aPD-1) therapy decreases the number of Arg1+ TAM while increasing Arg1- TAM; iv) accordingly, pharmacological inhibition of arginase 1 does not synergize with aPD-1 therapy. Conclusion: Overall, this research shows how powerful complementary single cell analytical approaches can be used to improve our understanding of drug action in vivo.

Author Info: (1) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (2) Center for Systems Biology, Massachusetts General Hospital, 18

Author Info: (1) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (2) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (3) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (4) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (5) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (6) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. (7) Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114. Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115.

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Unraveling the Mechanobiology of the Immune System

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Cells respond and actively adapt to environmental cues in the form of mechanical stimuli. This extends to immune cells and their critical role in the maintenance of tissue homeostasis. Multiple recent studies have begun illuminating underlying mechanisms of mechanosensation in modulating immune cell phenotypes. Since the extracellular microenvironment is critical to modify cellular physiology that ultimately determines the functionality of the cell, understanding the interactions between immune cells and their microenvironment is necessary. This review focuses on mechanoregulation of immune responses mediated by macrophages, dendritic cells, and T cells, in the context of modern mechanobiology.

Author Info: (1) KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea. (2) Department of Bioengineering, University of Washington, Seattle, WA

Author Info: (1) KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea. (2) Department of Bioengineering, University of Washington, Seattle, WA, 98109, USA. (3) KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea. (4) Department of Bioengineering, University of Washington, Seattle, WA, 98109, USA. (5) KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.

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Immunogenomic analysis reveals LGALS1 contributes to the immune heterogeneity and immunosuppression in glioma

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Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (2) Department of Neurosurgery

Author Info: (1) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (2) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (3) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (4) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (5) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (6) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (7) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. Neurosurgical department, Bashkir State Medical University, Ufa, 450008, Russia. (8) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (9) Neurosurgical department, Bashkir State Medical University, Ufa, 450008, Russia. (10) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. (11) Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.

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Cancer research in the era of immunogenomics

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The most meaningful advancement in cancer treatment in recent years has been the emergence of immunotherapy. Checkpoint inhibitor blockade and adoptive T cell therapy have shown remarkable clinical effects in a wide range of tumour types. Despite these advances, many tumours do not respond to these treatments, which raises the need to further investigate how patients can benefit from immunotherapy. This effort can now take advantage of the recent technological progress in single-cell, high-throughput sequencing and computational efforts. In this review, we will discuss advances in different immunotherapies and the principles of cancer immunogenomics, with an emphasis on the detection of cancer neoantigens with human leucocyte antigen peptidomics, and how these principles can be further used for more efficient clinical output.

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

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Altered frequency of CD8(+) CD11c(+) T cells and expression of immunosuppressive molecules in lymphoid organs of mouse model of colorectal cancer

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CD11c is a member of the beta2-integrin family typically used to define myeloid dendritic cells (DCs). Recent reports identify CD11c-expressing CD8(+) T cells as a new subset of CD8(+) regulatory T cells (Treg). Evidence exists that CD11c(+) CD8(+) T cells may exert their effector or regulatory functions under different conditions. To date, no studies have addressed the frequency of CD11c(+) T cells in cancer. Limited evidence exists in terms of expression of immune-checkpoint receptors, programmed cell death protein 1 (PD-1) and T-lymphocyte-associated antigen 4 (CTLA-4), as well as forkhead box P3 (Foxp3) in mouse lymphoid organs. Here, we have assessed CD11c(+) CD8(+) and CD11c(+) CD4(+) T cells, Foxp3, PD-1, and CTLA-4 expressing CD4(+) T cells and CD8(+) T cells in different tissues from three groups of male BALB/c mice-young, mature, and those with colorectal cancer (CRC). Analysis of CD3(+) CD11c(+) T cells in the bone marrow (BM), spleen, and lymph nodes (LN) in each group showed a higher percentage of CD3(+) CD11c(+) T cells in the BM from all groups and in the lymphoid organs of the cancer group compared with the young and mature groups. CD4(low) and CD4(high) cell fractions in mice BM have different expression patterns for Foxp3 and CTLA-4. We have observed a higher frequency of CD8(+) PD-1(+) T cells in the BM, spleen, and LN of CRC mice compared with normal mice. T-cell exhaustion is associated with inhibitory receptor PD-1. According to the regulatory roles of CD11c expression in CD8(+) T cells, we have proposed that the elevated percentage of CD11c, Foxp3, CTLA-4, and PD-1 expressing T cells were associated with immune response dysregulation in CRC.

Author Info: (1) Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of

Author Info: (1) Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. (2) Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. (3) Department of Sports Sciences, Shiraz University, Shiraz, Iran. (4) Department of Sports Sciences, Shiraz University, Shiraz, Iran. (5) Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. (6) Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. (7) Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. (8) Immunology Unit, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Head of Immunology Department, Medicine Faculty, Tabriz University of Medical Science, Tabriz, Iran.

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