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Zhang H, Li H, Qi Y, He J, Deng L, Chen S, Pan H, Guo H. IL17A/F secreted by ASCT2-overexpression ovarian cancer cells contributes to immune escape through the suppression of natural killer (NK) cells cytotoxicity by the activation of c-JUN/ PTGS2 pathway. Int Immunopharmacol 2025; 150:114226. [PMID: 39954656 DOI: 10.1016/j.intimp.2025.114226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/23/2025] [Accepted: 02/02/2025] [Indexed: 02/17/2025]
Abstract
Ovarian cancer (OC) is a deadly gynecologic cancer associated with metastasis, recurrence, and treatment resistance. The expression of the alanine-serine-cysteine transporter 2 (ASCT2) has been linked to poor prognosis and immune cell infiltration in OC tumors, but the underlying mechanisms are unclear. Lentiviral constructs were used to manipulate ASCT2 expression in OC cells (SKOV-3). The effects of ASCT2 on SKOV-3 behaviors including proliferation, invasion, migration, apoptosis, and cell cycle were assessed using various assays. The correlation between ASCT2 expression and immune infiltration in OC was analyzed using the Cancer Genome Atlas (TCGA) database. Co-culture experiments were conducted to evaluate the impact of ASCT2 overexpression in SKOV-3 on NK cells, followed by transcriptomics and cytokine analysis. ASCT2 expression and cytokine levels were characterized using qPCR and western blotting. ASCT2 overexpression significantly promoted cell proliferation, invasion, migration, and the percentage of G1-phase cells, while inhibiting apoptosis. ASCT2 silencing had the opposite effect. The expression of ASCT2 was negatively associated with NK cells in OC. ASCT2 overexpression in SKOV-3 cells led to excessive IL-17A/F production and inhibited the antitumor activity of NK cells, possibly through activating the IL-17 signaling pathway. The core regulatory genes c-JUN/PTGS2 in this pathway were upregulated, and antitumor cytokines were decreased in co-cultured NK cells, resulting in decreased antitumor activity and immune infiltration within the tumor. Our results suggest that overexpression of ASCT2 may play a predominant role in OC and NK cell immune infiltration within the tumor.
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Affiliation(s)
- Huixiang Zhang
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Library, Kunming Medical University, No.1168 West Chunrong Road, Chenggong District, Kunming, Yunnan 650500, China
| | - Haohan Li
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yanyan Qi
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Junhan He
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Langping Deng
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shipu Chen
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hong Pan
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Huiming Guo
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Li F, Gao C, Huang Y, Qiao Y, Xu H, Liu S, Wu H. Unraveling the breast cancer tumor microenvironment: crucial factors influencing natural killer cell function and therapeutic strategies. Int J Biol Sci 2025; 21:2606-2628. [PMID: 40303301 PMCID: PMC12035885 DOI: 10.7150/ijbs.108803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 03/04/2025] [Indexed: 05/02/2025] Open
Abstract
Natural killer (NK) cells have emerged as a novel and effective treatment for breast cancer. Nevertheless, the breast cancer tumor microenvironment (TME) manifests multiple immunosuppressive mechanisms, impeding the proper execution of NK cell functions. This review summarizes recent research on the influence of the TME on the functionality of NK cells in breast cancer. It delves into the effects of the internal environment of the TME on NK cells and elucidates the roles of diverse stromal components, immune cells, and signaling molecules in regulating NK cell activity within the TME. It also summarizes therapeutic strategies based on small-molecule inhibitors, antibody therapies, and natural products, as well as the progress of research in preclinical and clinical trials. By enhancing our understanding of the immunosuppressive TME and formulating strategies to counteract its effects, we could fully harness the therapeutic promise of NK cells in breast cancer treatment.
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Affiliation(s)
- Feifei Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunfang Gao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Huang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
| | - Yu Qiao
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
| | - Hongxiao Xu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Sheng Liu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huangan Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
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3
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Prasongtanakij S, Soontrapa K, Thumkeo D. The role of prostanoids in regulatory T cells and their implications in inflammatory diseases and cancers. Eur J Cell Biol 2025; 104:151482. [PMID: 40184828 DOI: 10.1016/j.ejcb.2025.151482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/05/2025] [Accepted: 03/11/2025] [Indexed: 04/07/2025] Open
Abstract
Regulatory T cells (Tregs) play an important role in the immune system through the regulation of immunological self-tolerance and homeostasis. Furthermore, increasing evidence suggests the potential contribution of Tregs beyond immunity in the process of repairing various injured tissues. Tregs are generally characterised by the constitutive expression of forkhead box protein 3 (FOXP3) transcription factor in the nucleus and high expression levels of CD25 and CTLA-4 on the cell surface. To date, a large number of molecules have been identified as key regulators of Treg differentiation and function. Among these molecules are prostanoids, which are multifaceted lipid mediators. Prostanoids are produced from arachidonic acid through the catalytic activity of the enzyme cyclooxygenase and exert their functions through the 9 cognate receptors, DP1-2, EP1-EP4, FP, IP and TP. We briefly review previous studies on the regulatory mechanism of Tregs and then discuss recent works on the modulatory role of prostanoids.
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Affiliation(s)
- Somsak Prasongtanakij
- Laboratory of Immunopharmacology, Kyoto University Graduate School of Medicine, Japan
| | - Kitipong Soontrapa
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand
| | - Dean Thumkeo
- Laboratory of Immunopharmacology, Kyoto University Graduate School of Medicine, Japan; Center for Medical Education and Internationalization, Kyoto University Faculty of Medicine, Japan.
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4
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Ielpo S, Barberini F, Dabbagh Moghaddam F, Pesce S, Cencioni C, Spallotta F, De Ninno A, Businaro L, Marcenaro E, Bei R, Cifaldi L, Barillari G, Melaiu O. Crosstalk and communication of cancer-associated fibroblasts with natural killer and dendritic cells: New frontiers and unveiled opportunities for cancer immunotherapy. Cancer Treat Rev 2024; 131:102843. [PMID: 39442289 DOI: 10.1016/j.ctrv.2024.102843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
Natural killer (NK) cells and dendritic cells (DCs) are critical mediators of anti-cancer immune responses. In addition to their individual roles, NK cells and DCs are involved in intercellular crosstalk which is essential for the initiation and coordination of adaptive immunity against cancer. However, NK cell and DC activity is often compromised in the tumor microenvironment (TME). Recently, much attention has been paid to one of the major components of the TME, the cancer-associated fibroblasts (CAFs), which not only contribute to extracellular matrix (ECM) deposition and tumor progression but also suppress immune cell functions. It is now well established that CAFs support T cell exclusion from tumor nests and regulate their cytotoxic activity. In contrast, little is currently known about their interaction with NK cells, and DCs. In this review, we describe the interaction of CAFs with NK cells and DCs, by secreting and expressing various mediators in the TME of adult solid tumors. We also provide a detailed overview of ongoing clinical studies evaluating the targeting of stromal factors alone or in combination with immunotherapy based on immune checkpoint inhibitors. Finally, we discuss currently available strategies for the selective depletion of detrimental CAFs and for a better understanding of their interaction with NK cells and DCs.
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Affiliation(s)
- Simone Ielpo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Barberini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Farnaz Dabbagh Moghaddam
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Silvia Pesce
- Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Chiara Cencioni
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (IASI-CNR), Rome, Italy
| | - Francesco Spallotta
- Department of Biology and Biotechnologies Charles Darwin, Sapienza University, 00185, Rome, Italy; Pasteur Institute Italy-Fondazione Cenci Bolognetti, Italy
| | - Adele De Ninno
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Luca Businaro
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
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5
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Roe K. Are secondary bacterial pneumonia mortalities increased because of insufficient pro-resolving mediators? J Infect Chemother 2024; 30:959-970. [PMID: 38977072 DOI: 10.1016/j.jiac.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/24/2024] [Accepted: 07/05/2024] [Indexed: 07/10/2024]
Abstract
Respiratory viral infections, including respiratory syncytial virus (RSV), parainfluenza viruses and type A and B influenza viruses, can have severe outcomes. Bacterial infections frequently follow viral infections, and influenza or other viral epidemics periodically have higher mortalities from secondary bacterial pneumonias. Most secondary bacterial infections can cause lung immunosuppression by fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, natural killer cells, dendritic cells and other lung immune cells. Bacterial infections induce synthesis of inflammatory mediators including prostaglandins and leukotrienes, then eventually also special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which normally resolve inflammation and immunosuppression. Concurrent viral and secondary bacterial infections are more dangerous, because viral infections can cause inflammation and immunosuppression before the secondary bacterial infections worsen inflammation and immunosuppression. Plausibly, the higher mortalities of secondary bacterial pneumonias are caused by the overwhelming inflammation and immunosuppression, which the special pro-resolving mediators might not resolve.
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Affiliation(s)
- Kevin Roe
- Retired United States Patent and Trademark Office, San Jose, CA, USA.
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6
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Rodríguez-Bejarano OH, Parra-López C, Patarroyo MA. A review concerning the breast cancer-related tumour microenvironment. Crit Rev Oncol Hematol 2024; 199:104389. [PMID: 38734280 DOI: 10.1016/j.critrevonc.2024.104389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
Breast cancer (BC) is currently the most common malignant tumour in women and one of the leading causes of their death around the world. New and increasingly personalised diagnostic and therapeutic tools have been introduced over the last few decades, along with significant advances regarding the study and knowledge related to BC. The tumour microenvironment (TME) refers to the tumour cell-associated cellular and molecular environment which can influence conditions affecting tumour development and progression. The TME is composed of immune cells, stromal cells, extracellular matrix (ECM) and signalling molecules secreted by these different cell types. Ever deeper understanding of TME composition changes during tumour development and progression will enable new and more innovative therapeutic strategies to become developed for targeting tumours during specific stages of its evolution. This review summarises the role of BC-related TME components and their influence on tumour progression and the development of resistance to therapy. In addition, an account on the modifications in BC-related TME components associated with therapy is given, and the completed or ongoing clinical trials related to this topic are presented.
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Affiliation(s)
- Oscar Hernán Rodríguez-Bejarano
- Health Sciences Faculty, Universidad de Ciencias Aplicadas y Ambientales (U.D.C.A), Calle 222#55-37, Bogotá 111166, Colombia; Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50#26-20, Bogotá 111321, Colombia; PhD Programme in Biotechnology, Faculty of Sciences, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia
| | - Carlos Parra-López
- Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia.
| | - Manuel Alfonso Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50#26-20, Bogotá 111321, Colombia; Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia.
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7
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Guo M, Hu P, Xie J, Tang K, Hu S, Sun J, He Y, Li J, Lu W, Liu H, Liu M, Yi Z, Peng S. Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4. Genes Dis 2024; 11:101164. [PMID: 38560505 PMCID: PMC10980949 DOI: 10.1016/j.gendis.2023.101164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/17/2023] [Accepted: 10/31/2023] [Indexed: 04/04/2024] Open
Abstract
Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.
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Affiliation(s)
- Mengmeng Guo
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Pan Hu
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jiayi Xie
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Kefu Tang
- Prenatal Diagnosis Center, Department of Clinical Laboratory, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai 200051, China
| | - Shixiu Hu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jialiang Sun
- Fengxian Hospital Affiliated to Southern Medical University, Shanghai 201400, China
| | - Yundong He
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jing Li
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Huirong Liu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Zhengfang Yi
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Shihong Peng
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
- Shanghai Yuyao Biotech Co., Ltd., Shanghai 200241, China
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8
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Roe K. Immunoregulatory natural killer cells. Clin Chim Acta 2024; 558:117896. [PMID: 38583553 DOI: 10.1016/j.cca.2024.117896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/09/2024]
Abstract
This review discusses a broader scope of functional roles for NK cells. Despite the well-known cytolytic and inflammatory roles of NK cells against tumors and pathogenic diseases, extensive evidence demonstrates certain subsets of NK cells have defacto immunoregulatory effects and have a role in inducing anergy or lysis of antigen-activated T cells and regulating several autoimmune diseases. Furthermore, recent evidence suggests certain subsets of immunoregulatory NK cells can cause anergy or lysis of antigen-activated T cells to regulate hyperinflammatory diseases, including multisystem inflammatory syndrome. Several pathogens induce T cell and NK cell exhaustion and/or suppression, which impair the immune system's control of the replication speed of virulent pathogens and tumors and result in extensive antigens and antigen-antibody immune complexes, potentially inducing to some extent a Type III hypersensitivity immune reaction. The Type III hypersensitivity immune reaction induces immune cell secretion of proteinases, which can cleave specific proteins to create autoantigens which activate T cells to initiate autoimmune and/or hyperinflammatory diseases. Furthermore, pathogen induced NK cell exhaustion and/or suppression will inhibit NK cells which would have induced the anergy or lysis of activated T cells to regulate autoimmune and hyperinflammatory diseases. Autoimmune and hyperinflammatory diseases can be consequences of the dual lymphocyte exhaustion and/or suppression effects during infections, by creating autoimmune and/or hyperinflammatory diseases, while also impairing immunoregulatory lymphocytes which otherwise would have regulated these diseases.
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Affiliation(s)
- Kevin Roe
- Retired USPTO, San Jose, CA, United States of America.
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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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Gao F, You X, Yang L, Zou X, Sui B. Boosting immune responses in lung tumor immune microenvironment: A comprehensive review of strategies and adjuvants. Int Rev Immunol 2024; 43:280-308. [PMID: 38525925 DOI: 10.1080/08830185.2024.2333275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/12/2024] [Accepted: 03/15/2024] [Indexed: 03/26/2024]
Abstract
The immune system has a substantial impact on the growth and expansion of lung malignancies. Immune cells are encompassed by a stroma comprising an extracellular matrix (ECM) and different cells like stromal cells, which are known as the tumor immune microenvironment (TIME). TME is marked by the presence of immunosuppressive factors, which inhibit the function of immune cells and expand tumor growth. In recent years, numerous strategies and adjuvants have been developed to extend immune responses in the TIME, to improve the efficacy of immunotherapy. In this comprehensive review, we outline the present knowledge of immune evasion mechanisms in lung TIME, explain the biology of immune cells and diverse effectors on these components, and discuss various approaches for overcoming suppressive barriers. We highlight the potential of novel adjuvants, including toll-like receptor (TLR) agonists, cytokines, phytochemicals, nanocarriers, and oncolytic viruses, for enhancing immune responses in the TME. Ultimately, we provide a summary of ongoing clinical trials investigating these strategies and adjuvants in lung cancer patients. This review also provides a broad overview of the current state-of-the-art in boosting immune responses in the TIME and highlights the potential of these approaches for improving outcomes in lung cancer patients.
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Affiliation(s)
- Fei Gao
- Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Xiaoqing You
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Liu Yang
- Department of Oncology, Da Qing Long Nan Hospital, Daqing, Heilongjiang Province, China
| | - Xiangni Zou
- Department of Nursing, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Bowen Sui
- Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
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11
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Olivera I, Luri-Rey C, Teijeira A, Eguren-Santamaria I, Gomis G, Palencia B, Berraondo P, Melero I. Facts and Hopes on Neutralization of Protumor Inflammatory Mediators in Cancer Immunotherapy. Clin Cancer Res 2023; 29:4711-4727. [PMID: 37522874 DOI: 10.1158/1078-0432.ccr-22-3653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/26/2023] [Accepted: 07/14/2023] [Indexed: 08/01/2023]
Abstract
In cancer pathogenesis, soluble mediators are responsible for a type of inflammation that favors the progression of tumors. The mechanisms chiefly involve changes in the cellular composition of the tumor tissue stroma and in the functional modulation of myeloid and lymphoid leukocytes. Active immunosuppression, proangiogenesis, changes in leukocyte traffic, extracellular matrix remodeling, and alterations in tumor-antigen presentation are the main mechanisms linked to the inflammation that fosters tumor growth and metastasis. Soluble inflammatory mediators and their receptors are amenable to various types of inhibitors that can be combined with other immunotherapy approaches. The main proinflammatory targets which can be interfered with at present and which are under preclinical and clinical development are IL1β, IL6, the CXCR1/2 chemokine axis, TNFα, VEGF, leukemia inhibitory factor, CCL2, IL35, and prostaglandins. In many instances, the corresponding neutralizing agents are already clinically available and can be repurposed as a result of their use in other areas of medicine such as autoimmune diseases and chronic inflammatory conditions.
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Affiliation(s)
- Irene Olivera
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Alvaro Teijeira
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Gabriel Gomis
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Belen Palencia
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Portillo AL, Monteiro JK, Rojas EA, Ritchie TM, Gillgrass A, Ashkar AA. Charting a killer course to the solid tumor: strategies to recruit and activate NK cells in the tumor microenvironment. Front Immunol 2023; 14:1286750. [PMID: 38022679 PMCID: PMC10663242 DOI: 10.3389/fimmu.2023.1286750] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
The ability to expand and activate natural Killer (NK) cells ex vivo has dramatically changed the landscape in the development of novel adoptive cell therapies for treating cancer over the last decade. NK cells have become a key player for cancer immunotherapy due to their innate ability to kill malignant cells while not harming healthy cells, allowing their potential use as an "off-the-shelf" product. Furthermore, recent advancements in NK cell genetic engineering methods have enabled the efficient generation of chimeric antigen receptor (CAR)-expressing NK cells that can exert both CAR-dependent and antigen-independent killing. Clinically, CAR-NK cells have shown promising efficacy and safety for treating CD19-expressing hematologic malignancies. While the number of pre-clinical studies using CAR-NK cells continues to expand, it is evident that solid tumors pose a unique challenge to NK cell-based adoptive cell therapies. Major barriers for efficacy include low NK cell trafficking and infiltration into solid tumor sites, low persistence, and immunosuppression by the harsh solid tumor microenvironment (TME). In this review we discuss the barriers posed by the solid tumor that prevent immune cell trafficking and NK cell effector functions. We then discuss promising strategies to enhance NK cell infiltration into solid tumor sites and activation within the TME. This includes NK cell-intrinsic and -extrinsic mechanisms such as NK cell engineering to resist TME-mediated inhibition and use of tumor-targeted agents such as oncolytic viruses expressing chemoattracting and activating payloads. We then discuss opportunities and challenges for using combination therapies to extend NK cell therapies for the treatment of solid tumors.
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Affiliation(s)
- Ana L. Portillo
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Jonathan K. Monteiro
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Eduardo A. Rojas
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Tyrah M. Ritchie
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Amy Gillgrass
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Ali A. Ashkar
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
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Kamal MV, Damerla RR, Dikhit PS, Kumar NAN. Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression and its association with genes regulating the VEGF signaling pathway in head and neck squamous cell carcinoma. J Oral Biol Craniofac Res 2023; 13:567-574. [PMID: 37559688 PMCID: PMC10407435 DOI: 10.1016/j.jobcr.2023.07.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/30/2023] [Accepted: 07/20/2023] [Indexed: 08/11/2023] Open
Abstract
Introduction The PTGS2 gene codes for the cyclooxygenase-2 (COX-2) enzyme that catalyzes the committed step in prostaglandin (PG) synthesis. Various in-vivo and in-vitro data suggest that prostaglandin E2 mediates as a signaling molecule for activating the VEGF signaling pathway (VSP), forming an association between COX-2 and VSP. Several chemotherapy regimens increasingly rely on preventing the synthesis of PGs. The targeted and metronomic chemotherapy agents, which suppress the COX-2 enzymes, have a major role in suppressing the oral cancer cascade. Hence, this study was designed to understand the pattern of PTGS2 expression and genes regulating VSP in head and neck cancers. Methods PTGS2 expression was analyzed in the TCGA database computationally with the help of the UALCAN web-server. The expression of VEGF signaling pathway genes was mined, and their expression pattern was determined. Co-expression analysis was done to elucidate the association between VEGF signaling genes and PTGS2. The ShineyGo web server was used for gene set enrichment. Results Significantly high PTGS2 expression was observed in tumor samples. Further genes regulating VEGF signaling were significantly overexpressed in tumor samples. Co-expression analysis results showed a significant positive correlation between PTGS2 and angiogenesis-regulating genes. The majority of the genes were enriched for angiogenesis pathways. Conclusion PTGS2 was significantly expressed in head and neck cancer, and its expression was associated with genes regulating angiogenesis.
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Affiliation(s)
- Mehta Vedant Kamal
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rama Rao Damerla
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Punit Singh Dikhit
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Naveena AN Kumar
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
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14
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Jalil AT, Abdulhadi MA, Al-Marzook FA, Hizam MM, Abdulameer SJ, Al-Azzawi AKJ, Zabibah RS, Fadhil AA. NK cells direct the perspective approaches to cancer immunotherapy. Med Oncol 2023; 40:206. [PMID: 37318610 DOI: 10.1007/s12032-023-02066-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 04/30/2023] [Indexed: 06/16/2023]
Abstract
Natural killer (NK) cells are innate immune cells with cytotoxic potentials to kill cancerous cells in several mechanisms, which could be implied for cancer therapy. While potent, their antitumor activities specially for solid tumors impaired by inadequate tumor infiltration, suppressive tumor microenvironment, cancer-associated stroma cells, and tumor-supportive immune cells. Therefore, manipulating or reprogramming these barriers by prospective strategies might improve current immunotherapies in the clinic or introduce novel NK-based immunotherapies. NK-based immunotherapy could be developed in monotherapy or in combination with other therapeutic regimens such as oncolytic virus therapy and immune checkpoint blockade, as presented in this review.
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Affiliation(s)
- Abduladheem Turki Jalil
- Department of Medical Laboratories Techniques, Al-Mustaqbal University College, Hilla, Babylon, Iraq.
| | - Mohanad Ali Abdulhadi
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Farah A Al-Marzook
- College of Medical and Health Technologies, Al-Zahraa University for Women, Karbala, 56100, Iraq
| | | | - Sada Jasim Abdulameer
- Biology Department, College of Education for Pure Science, Wasit University, Kut, Wasit, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ali A Fadhil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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15
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Chhichholiya Y, Ruthuparna M, Velagaleti H, Munshi A. Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood-brain barrier and treatment strategies. Clin Transl Oncol 2023; 25:1218-1241. [PMID: 36897508 DOI: 10.1007/s12094-022-03050-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/12/2022] [Indexed: 03/11/2023]
Abstract
Breast cancer (BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis (BM) reported in 17-20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood-brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length.
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Affiliation(s)
- Yogita Chhichholiya
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Malayil Ruthuparna
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Harini Velagaleti
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India.
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16
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Korbecki J, Rębacz-Maron E, Kupnicka P, Chlubek D, Baranowska-Bosiacka I. Synthesis and Significance of Arachidonic Acid, a Substrate for Cyclooxygenases, Lipoxygenases, and Cytochrome P450 Pathways in the Tumorigenesis of Glioblastoma Multiforme, Including a Pan-Cancer Comparative Analysis. Cancers (Basel) 2023; 15:cancers15030946. [PMID: 36765904 PMCID: PMC9913267 DOI: 10.3390/cancers15030946] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive gliomas. New and more effective therapeutic approaches are being sought based on studies of the various mechanisms of GBM tumorigenesis, including the synthesis and metabolism of arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA). PubMed, GEPIA, and the transcriptomics analysis carried out by Seifert et al. were used in writing this paper. In this paper, we discuss in detail the biosynthesis of this acid in GBM tumors, with a special focus on certain enzymes: fatty acid desaturase (FADS)1, FADS2, and elongation of long-chain fatty acids family member 5 (ELOVL5). We also discuss ARA metabolism, particularly its release from cell membrane phospholipids by phospholipase A2 (cPLA2, iPLA2, and sPLA2) and its processing by cyclooxygenases (COX-1 and COX-2), lipoxygenases (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2), and cytochrome P450. Next, we discuss the significance of lipid mediators synthesized from ARA in GBM cancer processes, including prostaglandins (PGE2, PGD2, and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2)), thromboxane A2 (TxA2), oxo-eicosatetraenoic acids, leukotrienes (LTB4, LTC4, LTD4, and LTE4), lipoxins, and many others. These lipid mediators can increase the proliferation of GBM cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Ewa Rębacz-Maron
- Department of Ecology and Anthropology, Institute of Biology, University of Szczecin, Wąska 13, 71-415 Szczecin, Poland
| | - Patrycja Kupnicka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
- Correspondence: ; Tel.: +48-914-661-515
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17
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Kamal MV, Rao M, Damerla RR, Pai A, Sharan K, Palod A, Shetty PS, Usman N, Kumar NAN. A Mechanistic Review of Methotrexate and Celecoxib as a Potential Metronomic Chemotherapy for Oral Squamous Cell Carcinoma. Cancer Invest 2023; 41:144-154. [PMID: 36269850 DOI: 10.1080/07357907.2022.2139840] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The combination of low-dose methotrexate and celecoxib as metronomic chemotherapy (MCT) is a novel therapy, believed to act by modulating the immune response, inhibiting angiogenesis and its cytotoxic action, though the exact mechanism of action is unclear. Clinically, MCT was found to be very effective in delaying tumor progression in patients with head and neck squamous cell carcinoma in both curative and palliative settings. This review was aimed to give a brief insight into the mechanism of action and potential molecular alterations of MCT in the treatment of oral cancers taking into consideration the various in vivo and in vitro studies.
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Affiliation(s)
- Mehta Vedant Kamal
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Rama Rao Damerla
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Ananth Pai
- Department of Medical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Krishan Sharan
- Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Akhil Palod
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Preethi S Shetty
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Nawaz Usman
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Naveena A N Kumar
- Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal, India
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18
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Wißfeld J, Werner A, Yan X, ten Bosch N, Cui G. Metabolic regulation of immune responses to cancer. Cancer Biol Med 2022; 19:j.issn.2095-3941.2022.0381. [PMID: 36269001 PMCID: PMC9724228 DOI: 10.20892/j.issn.2095-3941.2022.0381] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of "editing" metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.
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Affiliation(s)
- Jannis Wißfeld
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany,T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Anke Werner
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany,T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Xin Yan
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany,T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany
| | - Nora ten Bosch
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany,T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Guoliang Cui
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany,T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany,Correspondence to: Guoliang Cui, E-mail:
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19
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Tong L, Jiménez-Cortegana C, Tay AHM, Wickström S, Galluzzi L, Lundqvist A. NK cells and solid tumors: therapeutic potential and persisting obstacles. Mol Cancer 2022; 21:206. [PMID: 36319998 PMCID: PMC9623927 DOI: 10.1186/s12943-022-01672-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/10/2022] [Accepted: 09/24/2022] [Indexed: 11/05/2022] Open
Abstract
Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.
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Affiliation(s)
- Le Tong
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Carlos Jiménez-Cortegana
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Department of Medical Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Seville, Seville, Spain
| | - Apple H M Tay
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Department of Biological Science, Nanyang Technological University, Singapore, Singapore
| | - Stina Wickström
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
| | - Andreas Lundqvist
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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20
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Pi C, Jing P, Li B, Feng Y, Xu L, Xie K, Huang T, Xu X, Gu H, Fang J. Reversing PD-1 Resistance in B16F10 Cells and Recovering Tumour Immunity Using a COX2 Inhibitor. Cancers (Basel) 2022; 14:cancers14174134. [PMID: 36077671 PMCID: PMC9455073 DOI: 10.3390/cancers14174134] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/19/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed in various solid tumours, and prostaglandin E2 (PGE2) drives the development of malignant tumours. We developed a drug-resistant B16F10 (B16F10-R) tumour mouse model through four rounds of selection in vivo. Subsequently, we investigated changes in PD-L1 expression and lymphocyte infiltration in B16F10-NR and B16F10-R tumours. Additionally, we explored the role of COX2 in acquired resistance to pembrolizumab, an anti-PD-1 treatment. Immune cell infiltration was significantly decreased in resistant tumours compared to B16F10-NR tumours; however, ptgs2 gene expression was significantly elevated in resistant tumours. Aspirin or celecoxib combined with pembrolizumab can effectively reverse tumour drug resistance. In addition, ptgs2 knockout or the use of the EP4 inhibitor E7046 abrogated drug resistance to anti-PD-1 treatment in B16F10-R tumour cells. Our study showed that inhibition of the COX2/PGE2/EP4 axis could increase the number of immune cells infiltrating the tumour microenvironment and recover drug-resistant tumour sensitivity to pembrolizumab. Thus, we highlight COX2 inhibition as a promising therapeutic target for drug-resistant tumours for future consideration.
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Affiliation(s)
- Chenyu Pi
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Ping Jing
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Bingyu Li
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- College of Medicine, Henan University of Science and Technology, Luoyang 471000, China
| | - Yan Feng
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Lijun Xu
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- College of Medicine, Henan University of Science and Technology, Luoyang 471000, China
| | - Kun Xie
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Tao Huang
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xiaoqing Xu
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Hua Gu
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Correspondence: (H.G.); (J.F.); Tel.: +86-021-6598-2878 (H.G. & J.F.)
| | - Jianmin Fang
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Biomedical Research Center, Suzhou 230031, China
- Shanghai Tongji Hospital, Shanghai 200065, China
- Correspondence: (H.G.); (J.F.); Tel.: +86-021-6598-2878 (H.G. & J.F.)
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21
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Rethacker L, Boy M, Bisio V, Roussin F, Denizeau J, Vincent-Salomon A, Borcoman E, Sedlik C, Piaggio E, Toubert A, Dulphy N, Caignard A. Innate lymphoid cells: NK and cytotoxic ILC3 subsets infiltrate metastatic breast cancer lymph nodes. Oncoimmunology 2022; 11:2057396. [PMID: 35371620 PMCID: PMC8973349 DOI: 10.1080/2162402x.2022.2057396] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Innate lymphoid cells (ILCs) – which include cytotoxic Natural Killer (NK) cells and helper-type ILC – are important regulators of tissue immune homeostasis, with possible roles in tumor surveillance. We analyzed ILC and their functionality in human lymph nodes (LN). In LN, NK cells and ILC3 were the prominent subpopulations. Among the ILC3s, we identified a CD56+/ILC3 subset with a phenotype close to ILC3 but also expressing cytotoxicity genes shared with NK. In tumor-draining LNs (TD-LNs) and tumor samples from breast cancer (BC) patients, NK cells were prominent, and proportions of ILC3 subsets were low. In tumors and TD-LN, NK cells display reduced levels of NCR (Natural cytotoxicity receptors), despite high transcript levels and included a small subset CD127− CD56− NK cells with reduced function. Activated by cytokines CD56+/ILC3 cells from donor and patients LN acquired cytotoxic capacity and produced IFNg. In TD-LN, all cytokine activated ILC populations produced TNFα in response to BC cell line. Analyses of cytotoxic and helper ILC indicate a switch toward NK cells in TD-LN. The local tumor microenvironment inhibited NK cell functions through downregulation of NCR, but cytokine stimulation restored their functionality.
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Affiliation(s)
- Louise Rethacker
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - Maxime Boy
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - Valeria Bisio
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - France Roussin
- Service d’Anesthésie-Réanimation, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Jordan Denizeau
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Anne Vincent-Salomon
- Diagnostic and Theranostic Medicine Division, Institut Curie, PSL Research University, Paris, France
| | - Edith Borcoman
- Department of Medical Oncology, Institut Curie, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
| | - Christine Sedlik
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Eliane Piaggio
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Antoine Toubert
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
- Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Saint-Louis, Laboratoire d’Immunologie et Histocompatibilité, Paris, France
| | - Nicolas Dulphy
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
- Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Saint-Louis, Laboratoire d’Immunologie et Histocompatibilité, Paris, France
| | - Anne Caignard
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
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22
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Peña-Romero AC, Orenes-Piñero E. Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers. Cancers (Basel) 2022; 14:1681. [PMID: 35406451 PMCID: PMC8996887 DOI: 10.3390/cancers14071681] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 02/04/2023] Open
Abstract
Our body is constantly exposed to pathogens or external threats, but with the immune response that our body can develop, we can fight off and defeat possible attacks or infections. Nevertheless, sometimes this threat comes from an internal factor. Situations such as the existence of a tumour also cause our immune system (IS) to be put on alert. Indeed, the link between immunology and cancer is evident these days, with IS being used as one of the important targets for treating cancer. Our IS is able to eliminate those abnormal or damaged cells found in our body, preventing the uncontrolled proliferation of tumour cells that can lead to cancer. However, in several cases, tumour cells can escape from the IS. It has been observed that immune cells, the extracellular matrix, blood vessels, fat cells and various molecules could support tumour growth and development. Thus, the developing tumour receives structural support, irrigation and energy, among other resources, making its survival and progression possible. All these components that accompany and help the tumour to survive and to grow are called the tumour microenvironment (TME). Given the importance of its presence in the tumour development process, this review will focus on one of the components of the TME: immune cells. Immune cells can support anti-tumour immune response protecting us against tumour cells; nevertheless, they can also behave as pro-tumoural cells, thus promoting tumour progression and survival. In this review, the anti-tumour and pro-tumour immunity of several immune cells will be discussed. In addition, the TME influence on this dual effect will be also analysed.
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Affiliation(s)
| | - Esteban Orenes-Piñero
- Department of Biochemistry and Molecular Biology-A, University of Murcia, 30120 Murcia, Spain;
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23
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Hashim I, Al-Attar Z, Hamdan SJ. Aspirin Protective Effect on Cyclophosphamide Induced Hematological Toxicity. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Bone marrow toxicity is the most important factor limiting the use of cytotoxic drugs like alkylating agents in cancer treatment. Recently PG synthase enzyme inhibitors have been reported to potentiate the cytotoxic effects of these agents on cancer cells but little is known if they can affect the toxicity of these agents on bone marrow or other tissues. Cyclophosphamide is one of the most commonly used alkylating agent.
In the present work, the effect of these PG synthase enzyme inhibitors, aspirin on cyclophosphamide myelotoxicity was determined employing the peripheral blood count to reflect bone marrow injury. The effect on body weight changes caused by cyclophosphamide was also determined.
Cyclophosphamide in doses of 25, 50 and 75 mg/kg i. v. produced as a dose dependent reduction in total WBC count, granulocyte, non granulocyte, and Hb% which was maximum on second day after injection and still present on 5th day post injection. It also produced a dose dependent reduction in body weight on day 5 after injection.
Aspirin in doges of 75, 150 and 300 mg/kg i. m. protected against the reduction in WBC counts 'measured for 5 days after injection of cyclophosphamide (50 mg/kg). This protection was not dose dependent, though it was more optimum with 300 mg/kg and disappeared largely when a dose of 450 mg/kg was used. Aspirin did not prevent the changes in Hb% but retard the reduction in body weight caused by cyclophosphamide.
It is concluded that aspirin can help to reduce injury and enhance recovery from bone marrow toxicity caused by cytotoxic agents such as the alkylating drugs cyclophosphamide for which no specific antidote is available. Aspirin produces this effect possibly by eliminating the harmful inhibitory effect of excess PGs or leukotrienes, released by bone marrow injury on growth factors of haemopoietic progenitor cells.
The magnitude of this protection on WBC counts does not seem to differ between either PG synthase enzyme inhibitors or steroids when used alone or in combination although a synergistic effect in protecting erythropoiesis is observed.
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24
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Khalil HE, Ibrahim HIM, Ahmed EA, Emeka PM, Alhaider IA. Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a. Pharmaceuticals (Basel) 2022; 15:ph15020154. [PMID: 35215267 PMCID: PMC8876523 DOI: 10.3390/ph15020154] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/16/2022] [Accepted: 01/23/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to explain its regulation in cancer progression through an inflammatory mediator (COX-2) in A549 non-small lung cancer cell lines via in silico, mechanistic and molecular aspects. T. hamosa was extracted and then subjected to a CCK-8 cell viability assay in different cancer cell lines including MDA-MB-231, A549 and HCT-116. Total extract was subjected to several chromatographic techniques to yield orientin (OT); the structure was elucidated by inspection of NMR spectroscopic data. To achieve anticancer effects of OT, a cell viability assay using a CCK-8 kit, immunoprecipitation by Western blot, cell migration using a wound healing assay, cell invasion using a Matrigel-Transwell assay, apoptosis by AO/EB dual staining, flow cytometric analysis and DAPI staining, a silenced COX-2 model to determine PGE-2 production and real-time PCR and Western blot of BCL-2, CYP-1A1, iNOS and COX-2 markers were carried out. The results demonstrated that OT decreased the cell proliferation and controlled cell migration and invasive properties. OT destabilized the COX-2 mRNA and downregulated its expression in A549 cell lines. Virtual binding showed interaction (binding energy −10.43) between OT and COX-2 protein compared to the selective COX-2 inhibitor celecoxib (CLX) (binding energy −9.4). The OT-CLX combination showed a superior anticancer effect. The synergistic effect of OT-CLX combination was noticed in controlling the migration and invasion of A549 cell lines. OT-CLX downregulated the expression of BCL-2, iNOS and COX-2 and activated the proapoptotic gene CYP-1A1. OT mitigated the COX-2 expression via upregulation of miR-26b and miR-146a. Interestingly, COX-2-silenced transfected A549 cells exhibited reduced expression of miR-26b and miR-146a. The findings confirmed the direct interaction of OT with COX-2 protein. PGE-2 expression was quantified in both naïve and COX-2-silenced A549 cells. OT downregulated the release of PGE-2 in both tested conditions. These results confirmed the regulatory effect of OT on A549 cell growth in a COX-2-dependent manner. OT activated apoptosis via activation of CYP-1A1 expression in an independent manner. These results revealed that the OT-CLX combination could serve as a potential synergistic treatment for effective inflammatory-mediated anticancer strategies.
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Affiliation(s)
- Hany Ezzat Khalil
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
- Correspondence:
| | - Hairul-Islam Mohamed Ibrahim
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (H.-I.M.I.); (E.A.A.)
- Department of System Biology, Pondicherry Center for Biological Science and Educational Trust, Kottakuppam 605104, India
| | - Emad A. Ahmed
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (H.-I.M.I.); (E.A.A.)
- Lab of Molecular Physiology, Department of Zoology, Faculty of Science, Assiut University, Assiut 71515, Egypt
| | - Promise Madu Emeka
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
| | - Ibrahim A. Alhaider
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (P.M.E.); (I.A.A.)
- Research and Development, Saudi Food and Drug Authority, Riyadh 13312, Saudi Arabia
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25
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Wang Q, Morris RJ, Bode AM, Zhang T. Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy. Cancer Res 2021; 82:949-965. [PMID: 34949672 DOI: 10.1158/0008-5472.can-21-2297] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/27/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022]
Abstract
Because of profound effects observed in carcinogenesis, prostaglandins (PGs), prostaglandin-endoperoxide synthases, and PG receptors are implicated in cancer development and progression. Understanding the molecular mechanisms of PG actions has potential clinical relevance for cancer prevention and therapy. This review focuses on the current status of PG signaling pathways in modulating cancer progression and aims to provide insights into the mechanistic actions of PGs and their receptors in influencing tumor progression. We also examine several small molecules identified as having anticancer activity that target prostaglandin receptors. The literature suggests that targeting PG pathways could provide opportunities for cancer prevention and therapy.
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Affiliation(s)
- Qiushi Wang
- The Hormel Institute, University of Minnesota
| | | | - Ann M Bode
- The Hormel Institute, University of Minnesota
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26
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Yu Y, Gao L, Wang Y, Xu B, Maswikiti EP, Li H, Zheng P, Tao P, Xiang L, Gu B, Lucas A, Chen H. A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids. Front Oncol 2021; 11:751086. [PMID: 34722305 PMCID: PMC8551635 DOI: 10.3389/fonc.2021.751086] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/22/2021] [Indexed: 01/06/2023] Open
Abstract
In the past decade, cancer immunotherapy has achieved great success owing to the unravelling of unknown molecular forces in cancer immunity. However, it is critical that we address the limitations of current immunotherapy, including immune-related adverse events and drug resistance, and further enhance current immunotherapy. Lipids are reported to play important roles in modulating immune responses in cancer. Cancer cells use lipids to support their aggressive behaviour and allow immune evasion. Metabolic reprogramming of cancer cells destroys the equilibrium between lipid anabolism and catabolism, resulting in lipid accumulation within the tumour microenvironment (TME). Consequently, ubiquitous lipids, mainly fatty acids, within the TME can impact the function and phenotype of infiltrating immune cells. Determining the complex roles of lipids and their interactions with the TME will provide new insight for improving anti-tumour immune responses by targeting lipids. Herein, we present a review of recent literature that has demonstrated how lipid metabolism reprogramming occurs in cancer cells and influences cancer immunity. We also summarise the potential for lipid-based clinical translation to modify immune treatment.
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Affiliation(s)
- Yang Yu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yunpeng Wang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Bo Xu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Ewetse Paul Maswikiti
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Haiyuan Li
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Peng Zheng
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Pengxian Tao
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Lin Xiang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Baohong Gu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Alexandra Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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27
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Velichinskii RA, Streltsova MA, Kust SA, Sapozhnikov AM, Kovalenko EI. The Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors. Int J Mol Sci 2021; 22:ijms222111385. [PMID: 34768814 PMCID: PMC8584101 DOI: 10.3390/ijms222111385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/20/2022] Open
Abstract
NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based therapies are undergoing clinical trials and show considerable effectiveness for hematological tumors. In these types of cancers, the immune cells themselves often undergo malignant transformation, which determines the features of the disease. In contrast, the current use of NK cells as therapeutic agents for the treatment of solid tumors is much less promising. Most studies are at the stage of preclinical investigation, but few progress to clinical trials. Low efficiency of NK cell migration and functional activity in the tumor environment are currently considered the major barriers to NK cell anti-tumor therapies. Various therapeutic combinations, genetic engineering methods, alternative sources for obtaining NK cells, and other techniques are aiming at the development of promising NK cell anticancer therapies, regardless of tumorigenesis. In this review, we compare the role of NK cells in the pathogenesis of hematological and solid tumors and discuss current prospects of NK-cell-based therapy for hematological and solid tumors.
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28
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Market M, Tennakoon G, Auer RC. Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int J Mol Sci 2021; 22:ijms222111378. [PMID: 34768810 PMCID: PMC8583911 DOI: 10.3390/ijms222111378] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from surgical trauma serves to promote cancer recurrence and metastasis. The postoperative environment suppresses critical anti-tumor immune effector cells, including Natural Killer (NK) cells. The literature suggests that NK cells are critical mediators in the formation of metastases immediately following surgery. The following review will highlight the mechanisms that promote the formation of micrometastases by directly or indirectly inducing NK cell suppression following surgery. These include tissue hypoxia, neuroendocrine activation, hypercoagulation, the pro-inflammatory phase, and the anti-inflammatory phase. Perioperative therapeutic strategies designed to prevent or reverse NK cell dysfunction will also be examined for their potential to improve cancer outcomes by preventing surgery-induced metastases.
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Affiliation(s)
- Marisa Market
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
| | - Gayashan Tennakoon
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
| | - Rebecca C. Auer
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
- Department of General Surgery, The Ottawa Hospital, Ottawa, ON K1Y 4E9, Canada
- Correspondence: ; Tel.: +1-613-722-7000
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29
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Sorrin AJ, Liu C, Cicalo J, Reader J, Najafali D, Zhang Y, Roque DM, Huang HC. Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro. Cancers (Basel) 2021; 13:5259. [PMID: 34771424 PMCID: PMC8582354 DOI: 10.3390/cancers13215259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/05/2021] [Accepted: 10/10/2021] [Indexed: 12/11/2022] Open
Abstract
The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are "photodynamically primed", or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
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Affiliation(s)
- Aaron J. Sorrin
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Cindy Liu
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Julia Cicalo
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Jocelyn Reader
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (J.R.); (D.M.R.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
| | - Daniel Najafali
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Yuji Zhang
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Dana M. Roque
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (J.R.); (D.M.R.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
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30
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Fuertes MB, Domaica CI, Zwirner NW. Leveraging NKG2D Ligands in Immuno-Oncology. Front Immunol 2021; 12:713158. [PMID: 34394116 PMCID: PMC8358801 DOI: 10.3389/fimmu.2021.713158] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/02/2021] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.
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Affiliation(s)
- Mercedes Beatriz Fuertes
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Carolina Inés Domaica
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Norberto Walter Zwirner
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.,Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina
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31
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Wang Y, Cui L, Georgiev P, Singh L, Zheng Y, Yu Y, Grein J, Zhang C, Muise ES, Sloman DL, Ferguson H, Yu H, Pierre CS, Dakle PJ, Pucci V, Baker J, Loboda A, Linn D, Brynczka C, Wilson D, Haines BB, Long B, Wnek R, Sadekova S, Rosenzweig M, Haidle A, Han Y, Ranganath SH. Combination of EP 4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells. Oncoimmunology 2021; 10:1896643. [PMID: 33796403 PMCID: PMC7993229 DOI: 10.1080/2162402x.2021.1896643] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2–mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
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Affiliation(s)
- Yun Wang
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Long Cui
- Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Peter Georgiev
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Latika Singh
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Yanyan Zheng
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Ying Yu
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Jeff Grein
- Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Chunsheng Zhang
- Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Eric S Muise
- Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA
| | - David L Sloman
- Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Heidi Ferguson
- Department of Pharmaceutical Science, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Hongshi Yu
- Department of Pharmaceutical Science, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Cristina St Pierre
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Pranal J Dakle
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Vincenzo Pucci
- Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts, USA
| | - James Baker
- Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Andrey Loboda
- Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Doug Linn
- Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Christopher Brynczka
- Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Doug Wilson
- Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Brian B Haines
- Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Brian Long
- Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Richard Wnek
- Department of Translational Biomarkers, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Svetlana Sadekova
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Michael Rosenzweig
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Andrew Haidle
- Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Yongxin Han
- Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA
| | - Sheila H Ranganath
- Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA
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32
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Pu D, Yin L, Huang L, Qin C, Zhou Y, Wu Q, Li Y, Zhou Q, Li L. Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer. Front Oncol 2021; 11:637504. [PMID: 33718229 PMCID: PMC7952860 DOI: 10.3389/fonc.2021.637504] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/20/2021] [Indexed: 02/05/2023] Open
Abstract
The clinical application of immunotherapy is the milestone of cancer treatment. However, some patients have bad reaction. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple cancer cells and is associated with poor prognosis. It is the key enzyme of prostaglandin E2 (PGE2) that has been proved to promote the development, proliferation and metastasis of tumor cells. Recent studies further find the PGE2 in tumor microenvironment (TME) actively triggers tumor immune evasion via many ways, leading to poor response of immunotherapy. COX-2 inhibitor is suggested to restrain the immunosuppression of PGE2 and may enhance or reverse the response of immune checkpoint inhibitors (ICIs). This review provides insight into the mechanism of COX-2/PGE2 signal in immunosuppressive TME and summarizes the clinical application and trials in cancer treatment.
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Affiliation(s)
- Dan Pu
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Liyuan Yin
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Huang
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Changlong Qin
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Oncology Department, West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Wu
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Li
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qinghua Zhou
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Li
- Department of Lung Cancer Center, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis. Cancers (Basel) 2021; 13:cancers13050942. [PMID: 33668160 PMCID: PMC7956318 DOI: 10.3390/cancers13050942] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.
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34
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Vleeshouwers W, van den Dries K, de Keijzer S, Joosten B, Lidke DS, Cambi A. Characterization of the Signaling Modalities of Prostaglandin E2 Receptors EP2 and EP4 Reveals Crosstalk and a Role for Microtubules. Front Immunol 2021; 11:613286. [PMID: 33643295 PMCID: PMC7907432 DOI: 10.3389/fimmu.2020.613286] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/18/2020] [Indexed: 11/13/2022] Open
Abstract
Prostaglandin E2 (PGE2) is a lipid mediator that modulates the function of myeloid immune cells such as macrophages and dendritic cells (DCs) through the activation of the G protein-coupled receptors EP2 and EP4. While both EP2 and EP4 signaling leads to an elevation of intracellular cyclic adenosine monophosphate (cAMP) levels through the stimulating Gαs protein, EP4 also couples to the inhibitory Gαi protein to decrease the production of cAMP. The receptor-specific contributions to downstream immune modulatory functions are still poorly defined. Here, we employed quantitative imaging methods to characterize the early EP2 and EP4 signaling events in myeloid cells and their contribution to the dissolution of adhesion structures called podosomes, which is a first and essential step in DC maturation. We first show that podosome loss in DCs is primarily mediated by EP4. Next, we demonstrate that EP2 and EP4 signaling leads to distinct cAMP production profiles, with EP4 inducing a transient cAMP response and EP2 inducing a sustained cAMP response only at high PGE2 levels. We further find that simultaneous EP2 and EP4 stimulation attenuates cAMP production, suggesting a reciprocal control of EP2 and EP4 signaling. Finally, we demonstrate that efficient signaling of both EP2 and EP4 relies on an intact microtubule network. Together, these results enhance our understanding of early EP2 and EP4 signaling in myeloid cells. Considering that modulation of PGE2 signaling is regarded as an important therapeutic possibility in anti-tumor immunotherapy, our findings may facilitate the development of efficient and specific immune modulators of PGE2 receptors.
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Affiliation(s)
- Ward Vleeshouwers
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Koen van den Dries
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Sandra de Keijzer
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Ben Joosten
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Diane S Lidke
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.,Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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35
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Riggan L, Shah S, O’Sullivan TE. Arrested development: suppression of NK cell function in the tumor microenvironment. Clin Transl Immunology 2021; 10:e1238. [PMID: 33456775 PMCID: PMC7797224 DOI: 10.1002/cti2.1238] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that protect against viral infection and tumor metastasis. Despite their inherent ability to kill a broad range of virally infected, stressed and transformed cells, low numbers of dysfunctional NK cells are often observed in many advanced solid human cancers. Here, we review the potential mechanisms that influence suboptimal mature NK cell recruitment and function in the tumor microenvironment (TME) of solid tumors. We further highlight current immunotherapy approaches aimed to circumvent NK cell dysfunction and discuss next-generation strategies to enhance adoptive NK cell therapy through targeting intrinsic and extrinsic checkpoints the regulate NK cell functionality in the TME. Understanding the mechanisms that drive NK cell dysfunction in the TME will lead to novel immunotherapeutic approaches in the fight against cancer.
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Affiliation(s)
- Luke Riggan
- Department of Microbiology, Immunology, and Molecular GeneticsDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Molecular Biology InstituteUniversity of CaliforniaLos AngelesCAUSA
| | - Siya Shah
- Department of Microbiology, Immunology, and Molecular GeneticsDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - Timothy E O’Sullivan
- Department of Microbiology, Immunology, and Molecular GeneticsDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Molecular Biology InstituteUniversity of CaliforniaLos AngelesCAUSA
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36
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Fiore PF, Vacca P, Tumino N, Besi F, Pelosi A, Munari E, Marconi M, Caruana I, Pistoia V, Moretta L, Azzarone B. Wilms' Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages. Cancers (Basel) 2021; 13:E224. [PMID: 33435455 PMCID: PMC7826641 DOI: 10.3390/cancers13020224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 12/30/2020] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm's Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56+/CD133-) or an epithelial (CD56-/CD133+) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.
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Affiliation(s)
- Piera Filomena Fiore
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Paola Vacca
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Nicola Tumino
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Francesca Besi
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Andrea Pelosi
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Enrico Munari
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy;
| | - Marcella Marconi
- Department of Pathology, IRCCS Sacro Cuore Don Calabria, Negrar, 37024 Verona, Italy;
| | - Ignazio Caruana
- Department of Paediatric Haematology, Oncology and Stem Cell Transplantation University Children’s Hospital of Würzburg, 97080 Würzburg, Germany;
| | - Vito Pistoia
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Lorenzo Moretta
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
| | - Bruno Azzarone
- Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (P.F.F.); (P.V.); (N.T.); (F.B.); (A.P.); (V.P.)
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37
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Finetti F, Travelli C, Ercoli J, Colombo G, Buoso E, Trabalzini L. Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity. BIOLOGY 2020; 9:E434. [PMID: 33271839 PMCID: PMC7760298 DOI: 10.3390/biology9120434] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/27/2020] [Accepted: 11/29/2020] [Indexed: 12/13/2022]
Abstract
The involvement of inflammation in cancer progression has been the subject of research for many years. Inflammatory milieu and immune response are associated with cancer progression and recurrence. In different types of tumors, growth and metastatic phenotype characterized by the epithelial mesenchymal transition (EMT) process, stemness, and angiogenesis, are increasingly associated with intrinsic or extrinsic inflammation. Among the inflammatory mediators, prostaglandin E2 (PGE2) supports epithelial tumor aggressiveness by several mechanisms, including growth promotion, escape from apoptosis, transactivation of tyrosine kinase growth factor receptors, and induction of angiogenesis. Moreover, PGE2 is an important player in the tumor microenvironment, where it suppresses antitumor immunity and regulates tumor immune evasion, leading to increased tumoral progression. In this review, we describe the current knowledge on the pro-tumoral activity of PGE2 focusing on its role in cancer progression and in the regulation of the tumor microenvironment.
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Affiliation(s)
- Federica Finetti
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Cristina Travelli
- Department of Pharmaceutical Sciences, University of Pavia, 27100 Pavia, Italy; (C.T.); (E.B.)
| | - Jasmine Ercoli
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Giorgia Colombo
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy;
| | - Erica Buoso
- Department of Pharmaceutical Sciences, University of Pavia, 27100 Pavia, Italy; (C.T.); (E.B.)
| | - Lorenza Trabalzini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
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38
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Arianfar E, Shahgordi S, Memarian A. Natural Killer Cell Defects in Breast Cancer: A Key Pathway for Tumor Evasion. Int Rev Immunol 2020; 40:197-216. [PMID: 33258393 DOI: 10.1080/08830185.2020.1845670] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As the most important innate immune component cancers invader, natural killer (NK) cells have a magnificent role in antitumor immunity without any prior sensitization. Different subsets of NK cells have distinct responses during tumor cell exposure, according to their phenotypes and environments. Their function is induced mainly by the activity of both inhibitory and activating receptors against cancerous cells. Since the immunosuppression in the tumor microenvironment of breast cancer patients has directly deteriorated the phenotype and disturbed the function of NK cells, recruiting compensatory mechanisms indicate promising outcomes for immunotherapeutic approaches. These evidences accentuate the importance of NK cell distinct features in protection against breast tumors. In this review, we discuss the several mechanisms involved in NK cells suppression which consequently promote tumor progression and disease recurrence in patients with breast cancer.
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Affiliation(s)
- Elaheh Arianfar
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sanaz Shahgordi
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.,Immunology department, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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39
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Domagala J, Lachota M, Klopotowska M, Graczyk-Jarzynka A, Domagala A, Zhylko A, Soroczynska K, Winiarska M. The Tumor Microenvironment-A Metabolic Obstacle to NK Cells' Activity. Cancers (Basel) 2020; 12:cancers12123542. [PMID: 33260925 PMCID: PMC7761432 DOI: 10.3390/cancers12123542] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023] Open
Abstract
NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.
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Affiliation(s)
- Joanna Domagala
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (J.D.); (A.G.-J.); (A.Z.); (K.S.)
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Mieszko Lachota
- Department of Clinical Immunology, Medical University of Warsaw, 02-006 Warsaw, Poland; (M.L.); (M.K.)
| | - Marta Klopotowska
- Department of Clinical Immunology, Medical University of Warsaw, 02-006 Warsaw, Poland; (M.L.); (M.K.)
| | - Agnieszka Graczyk-Jarzynka
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (J.D.); (A.G.-J.); (A.Z.); (K.S.)
| | - Antoni Domagala
- Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University of Kielce, 25-317 Kielce, Poland;
- Department of Urology, Holy Cross Cancer Center, 25-734 Kielce, Poland
| | - Andriy Zhylko
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (J.D.); (A.G.-J.); (A.Z.); (K.S.)
| | - Karolina Soroczynska
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (J.D.); (A.G.-J.); (A.Z.); (K.S.)
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Magdalena Winiarska
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (J.D.); (A.G.-J.); (A.Z.); (K.S.)
- Correspondence: ; Tel.: +48-225-992-199
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40
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Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells. Int J Biol Macromol 2020; 167:1006-1019. [PMID: 33227333 DOI: 10.1016/j.ijbiomac.2020.11.056] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/02/2020] [Accepted: 11/09/2020] [Indexed: 12/19/2022]
Abstract
Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat cancer cells and assessed the effect of combination therapy on cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on cancer cells could deliver siRNAs to cancer cells and significantly suppress the HIF-1α in them. Combination therapy of cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the cancer cells, remarkably.
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41
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NK Cell Adoptive Immunotherapy of Cancer: Evaluating Recognition Strategies and Overcoming Limitations. Transplant Cell Ther 2020; 27:21-35. [PMID: 33007496 DOI: 10.1016/j.bbmt.2020.09.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/14/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023]
Abstract
Natural killer (NK) cells, the primary effector cells of the innate immune system, utilize multiple strategies to recognize tumor cells by (1) detecting the presence of activating receptor ligands, which are often upregulated in cancer; (2) targeting cells that have a loss of major histocompatibility complex (MHC); and (3) binding to antibodies that bind to tumor-specific antigens on the tumor cell surface. All these strategies have been successfully harnessed in adoptive NK cell immunotherapies targeting cancer. In this review, we review the applications of NK cell therapies across different tumor types. Similar to other forms of immunotherapy, tumor-induced immune escape and immune suppression can limit NK cell therapies' efficacy. Therefore, we also discuss how these limitations can be overcome by conferring NK cells with the ability to redirect their tumor-targeting capabilities and survive the immune-suppressive tumor microenvironment. Finally, we also discuss how future iterations can benefit from combination therapies with other immunotherapeutic agents.
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42
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Anderson G, Carbone A, Mazzoccoli G. Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress. BIOLOGY 2020; 9:E249. [PMID: 32867244 PMCID: PMC7564943 DOI: 10.3390/biology9090249] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022]
Abstract
There is an under-recognized role of the aryl hydrocarbon receptor (AhR) in co-ordinating the entry and pathophysiology of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that underpins the COVID-19 pandemic. The rise in pro-inflammatory cytokines during the 'cytokine storm' induce indoleamine 2,3-dioxygenase (IDO), leading to an increase in kynurenine that activates the AhR, thereby heightening the initial pro-inflammatory cytokine phase and suppressing the endogenous anti-viral response. Such AhR-driven changes underpin the heightened severity and fatality associated with pre-existent high-risk medical conditions, such as type II diabetes, as well as to how racial discrimination stress contributes to the raised severity/fatality in people from the Black Asian and Minority Ethnic (BAME) communities. The AhR is pivotal in modulating mitochondrial metabolism and co-ordinating specialized, pro-resolving mediators (SPMs), the melatonergic pathways, acetyl-coenzyme A, and the cyclooxygenase (COX) 2-prostaglandin (PG) E2 pathway that underpin 'exhaustion' in the endogenous anti-viral cells, paralleling similar metabolic suppression in cytolytic immune cells that is evident across all cancers. The pro-inflammatory cytokine induced gut permeability/dysbiosis and suppression of pineal melatonin are aspects of the wider pathophysiological underpinnings regulated by the AhR. This has a number of prophylactic and treatment implications for SARS-CoV-2 infection and cancers and future research directions that better investigate the biological underpinnings of social processes and how these may drive health disparities.
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Affiliation(s)
- George Anderson
- CRC Scotland & London, Eccleston Square, London SW1V 1PB, UK;
| | - Annalucia Carbone
- Division of Internal Medicine and Chronobiology Laboratory, Department of Medical Sciences, Fondazione IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, 71013 Foggia, Italy;
| | - Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Laboratory, Department of Medical Sciences, Fondazione IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, 71013 Foggia, Italy;
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43
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Li Y, Li J, Dong J, Zhang L, Liu D, He J, She Y, Ma C, Liu Y. 15-PGDH Expression in Gastric Cancer: A Potential Role in Anti-Tumor Immunity. Cancer Manag Res 2020; 12:7419-7426. [PMID: 32884353 PMCID: PMC7443415 DOI: 10.2147/cmar.s245726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 07/30/2020] [Indexed: 11/23/2022] Open
Abstract
Introduction Host immunity plays a vital role in tumorigenesis, including in tumor invasion and metastasis. However, the precise underlying mechanism remains to be explored. The enzyme 15-PGDH, which plays a key role in prostaglandin degradation, is a critical inflammatory mediator in gastric cancer (GC) tumorigenesis. Materials and Methods Immunohistochemistry was performed to determine 15-PGDH expression in GC and the corresponding adjacent non-neoplastic tissues (n=92). Results The expression of 15-PGDH in GC tissues was significantly lower than that in paracancerous tissues (P<0.001) and found to correspond inversely with GC differentiation (P=0.043) and lymph node metastasis (P=0.046). In contrast, FOXP3 expression was increased in poorly differentiated GC tissues (P=0.001). Kaplan–Meier analysis revealed that GC patients with low expression of 15-PGDH (Log rank test, P=0.007) and high expression of FOXP3 (Log rank test, P=0.009) had shorter overall survival (OS) than those with high 15-PGDH and low FOXP3 expression. OS was also correlated with pathological tumor-node-metastasis stage (Log rank test, P=0.014). Furthermore, using Cox proportional hazard regression, 15-PGDH expression [hazard ratio (HR): 0.605 (0.440–0.833); P=0.002] was identified as an independent factor for OS. Conclusion Our data suggest that 15-PGDH may contribute to anti-tumor immunity by regulating FOXP3+ Treg cells. The findings are useful for the identification of therapeutic targets for the management of GC.
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Affiliation(s)
- Yaling Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
| | - Junjie Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Juanjuan Dong
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Lei Zhang
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Dongling Liu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Jianzheng He
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
| | - Yali She
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Chengxu Ma
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Yongqi Liu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
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44
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Ching MM, Reader J, Fulton AM. Eicosanoids in Cancer: Prostaglandin E 2 Receptor 4 in Cancer Therapeutics and Immunotherapy. Front Pharmacol 2020; 11:819. [PMID: 32547404 PMCID: PMC7273839 DOI: 10.3389/fphar.2020.00819] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/19/2020] [Indexed: 12/17/2022] Open
Abstract
The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-κB. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immune-based therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies.
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Affiliation(s)
- Mc Millan Ching
- Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jocelyn Reader
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Baltimore, MD, United States
| | - Amy M. Fulton
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Baltimore, MD, United States
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, United States
- Baltimore Veterans Administration Medical Center, Baltimore, MD, United States
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45
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van der Zanden SY, Luimstra JJ, Neefjes J, Borst J, Ovaa H. Opportunities for Small Molecules in Cancer Immunotherapy. Trends Immunol 2020; 41:493-511. [PMID: 32381382 DOI: 10.1016/j.it.2020.04.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 04/06/2020] [Accepted: 04/06/2020] [Indexed: 01/08/2023]
Abstract
Cancer immunotherapy has proven remarkably successful through instigation of systemic antitumor T cell responses. Despite this achievement, further advancements are needed to expand the scope of susceptible cancer types and overcome variation in treatment outcomes between patients. Small-molecule drugs targeting defined pathways and/or cells capable of immune modulation are expected to substantially improve efficacy of cancer immunotherapy. Small-molecule drugs possess unique properties compatible with systemic administration and amenable to both extracellular and intracellular targets. These compounds can modify molecular pathways to overcome immune tolerance and suppression towards effective antitumor responses. Here, we provide an overview of how such effects might be achieved by combining immunotherapy with conventional and/or new small-molecule chemotherapeutics.
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Affiliation(s)
- Sabina Y van der Zanden
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Oncode Institute, Utrecht, The Netherlands
| | - Jolien J Luimstra
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Oncode Institute, Utrecht, The Netherlands
| | - Jacques Neefjes
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
| | - Jannie Borst
- Oncode Institute, Utrecht, The Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Huib Ovaa
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
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Take Y, Koizumi S, Nagahisa A. Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action. Front Immunol 2020; 11:324. [PMID: 32210957 PMCID: PMC7076081 DOI: 10.3389/fimmu.2020.00324] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 02/10/2020] [Indexed: 12/20/2022] Open
Abstract
A highly expressed prostaglandin E2 (PGE2) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression. In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE2 receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. This review summarizes PGE2/EP4 signal inhibition in relation to the cancer-immunity cycle (C-IC), which describes fundamental tumor-immune interactions in cancer immunotherapy. PGE2 is suggested to slow down C-IC by inhibiting natural killer cell functions, suppressing the supply of conventional dendritic cell precursors to the TME. This is critical for the tumor-associated antigen priming of CD8+ T cells and their translocation to the tumor tissue from the tumor-draining lymph node. Furthermore, PGE2 activates several key immune-suppressive cells present in tumors and counteracts tumoricidal properties of the effector CD8+ T cells. These effects of PGE2 drive the tumors to non-T-cell-inflamed tumors and cause refractory conditions to cancer immunotherapies, e.g., immune checkpoint inhibitor (ICI) treatment. EP4 antagonist therapy is suggested to inhibit the immune-suppressive and tumorigenic roles of PGE2 in tumors, and it may sensitize the therapeutic effects of ICIs in patients with non-inflamed and C-IC-deficient tumors. This review provides insight into the mechanism of action of EP4 antagonists in cancer immunotherapy and suggests a C-IC modulating opportunity for EP4 antagonist therapy in combination with ICIs and/or other cancer therapies.
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Melaiu O, Lucarini V, Cifaldi L, Fruci D. Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. Front Immunol 2020; 10:3038. [PMID: 32038612 PMCID: PMC6985149 DOI: 10.3389/fimmu.2019.03038] [Citation(s) in RCA: 288] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022] Open
Abstract
Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.
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Affiliation(s)
- Ombretta Melaiu
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy.,Department of Biology, University of Pisa, Pisa, Italy
| | - Valeria Lucarini
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Loredana Cifaldi
- Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Doriana Fruci
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy
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Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer. Cancer Metastasis Rev 2019; 37:369-384. [PMID: 29858743 DOI: 10.1007/s10555-018-9734-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Lymphangiogenesis (formation of new lymphatic vessels), unlike angiogenesis, has been a lesser-focused field in cancer biology, because of earlier controversy regarding whether lymphatic metastasis occurs via pre-existing or newly formed lymphatics. Recent evidence reveals that peri-tumoral or intra-tumoral lymphangiogenesis is a precursor for lymphatic metastasis in most carcinomas and melanomas. Two major lymphangiogenic factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, are produced by cancer cells or immune cells such as macrophages in the tumor-stroma to promote sprouting of lymphatics from lymphatic endothelial cells (LEC) or LEC precursors (LECP) by binding to their primary (high affinity) receptor VEGF-R3 or secondary receptors VEGF-R2, neuropilin (NRP)2 and α9/β1 integrin. Many other growth factors/receptors such as VEGF-A/VEGF-R2, fibroblast growth factor (FGF)2/FGF-R, platelet-derived growth factor (PDGF)/PDGF-R, hepatocyte growth factor (HGF)/C-Met, angiopoietins (Ang)1, 2/Tie2, and chemokines/ chemokine receptors (CCL21/CCR7, CCL12/CCR4) can also stimulate LEC sprouting directly or indirectly. This review deals with the roles of prostaglandins (PG), in particular PGE2, in cancer-associated lymphangiogenesis, with special emphasis on breast cancer. We show that cyclooxygenase (COX)-2 expression by breast cancer cells or tumor stroma leading to high PGE2 levels in the tumor milieu promotes lymphangiogenesis and lymphatic metastases, resulting from binding of PGE2 to PGE receptors (EP, in particular EP4) on multiple cell types: tumor cells, tumor-infiltrating immune cells, and LEC. EP4 activation on cancer cells and macrophages upregulated VEGF-C/D production to stimulate LEC sprouting. Furthermore, ligation of EP4 with PGE2 on cancer or host cells can initiate a new cascade of molecular events leading to cross-talk between cancer cells and LEC, facilitating lymphangiogenesis and lympho-vascular transport of cancer cells. We make a case for EP4 as a potential therapeutic target for breast cancer.
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The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction. Cancers (Basel) 2018; 11:cancers11010002. [PMID: 30577463 PMCID: PMC6356325 DOI: 10.3390/cancers11010002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 12/10/2018] [Accepted: 12/17/2018] [Indexed: 12/22/2022] Open
Abstract
Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.
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50
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Frazao A, Messaoudene M, Nunez N, Dulphy N, Roussin F, Sedlik C, Zitvogel L, Piaggio E, Toubert A, Caignard A. CD16 +NKG2A high Natural Killer Cells Infiltrate Breast Cancer-Draining Lymph Nodes. Cancer Immunol Res 2018; 7:208-218. [PMID: 30514793 DOI: 10.1158/2326-6066.cir-18-0085] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 07/03/2018] [Accepted: 11/27/2018] [Indexed: 11/16/2022]
Abstract
Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer. Natural killer (NK) cells that infiltrate TD-LNs [including noninvaded (NI) or metastatic (M)-LNs from breast cancer patients] and NK cells from healthy donor (HD)-LNs were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared with HD-LN NK cells. Compared with HD-LNs, TD-LN NK cells expressed activating DNAM-1, NKG2C and inhibitory NKG2A receptors, and exhibited elevated CXCR3 expression. CD16, NKG2A, and NKp46 expression were shown to be increased in stage IIIA breast cancer patients. TD-LNs contained a large proportion of activated CD56brightCD16+ NK cells with high expression of NKG2A. We also showed that a subset of LN NK cells expressed PD-1, expression of which was correlated with NKp30 and NKG2C expression. LN NK cell activation status was evaluated by degranulation potential and lytic capacity toward breast cancer cells. NK cells from TD-LNs degranulated after coculture with breast cancer cell lines. Cytokine-activated TD-LN NK cells exerted greater lysis of breast cancer cell lines than HD-LN NK cells and preferentially lysed the HLA class Ilow MCF-7 breast cancer cell line. TD-LNs from breast cancer patients, thus, contained activated lytic NK cells. The expression of inhibitory receptor NKG2A and checkpoint PD-1 by NK cells infiltrating breast cancer-draining LNs supports their potential as targets for immunotherapies using anti-NKG2A and/or anti-PD-1.
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Affiliation(s)
- Alexandra Frazao
- INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.,Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France
| | - Meriem Messaoudene
- INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.,Gustave Roussy Cancer Campus (GRCC), Villejuif, France
| | - Nicolas Nunez
- Institut Curie, PSL Research University, INSERM U932, Paris, France.,Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France
| | - Nicolas Dulphy
- INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.,Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.,Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris, France
| | - France Roussin
- Service d'Anesthésie-Réanimation, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Christine Sedlik
- Institut Curie, PSL Research University, INSERM U932, Paris, France.,Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France.,Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Villejuif, France.,Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.,Univ. Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France
| | - Eliane Piaggio
- Institut Curie, PSL Research University, INSERM U932, Paris, France.,Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France
| | - Antoine Toubert
- INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.,Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.,Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris, France
| | - Anne Caignard
- INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France.
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