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Imani S, Jabbarzadeh Kaboli P, Babaeizad A, Maghsoudloo M. Neoantigen mRNA vaccines and A 2A receptor antagonism: A strategy to enhance T cell immunity. Hum Vaccin Immunother 2025; 21:2458936. [PMID: 39882781 PMCID: PMC11784654 DOI: 10.1080/21645515.2025.2458936] [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: 12/05/2024] [Revised: 01/19/2025] [Accepted: 01/23/2025] [Indexed: 01/31/2025] Open
Abstract
Although neo-antigen mRNA vaccines are promising for personalized cancer therapy, their effectiveness is often limited by the immunosuppressive tumor microenvironment (TME). The adenosine A2A receptor (A2AR) inhibits dendritic cell (DC) function and weakens antitumor T cell responses through hypoxia-driven mechanisms within the TME. This review explores a novel strategy combining neo-antigen mRNA vaccines with A2AR antagonists (A2ARi). By targeting A2AR, this approach reduces TME-induced immunosuppression, enhances DC activation, and improves neo-antigen presentation. The review also discusses lipid nanoparticles (LNPs) to co-deliver A2ARi and mRNA vaccines, optimizing their effectiveness. The integration of neo-antigen mRNA-LNPs with A2ARi modulation offers a promising strategy to overcome immunosuppression, stimulate DC activation, and achieve precise anti-tumor responses with minimal off-target effects. This synergy represents significant progress in cancer immunotherapy, advancing the potential for personalized neoantigen therapies.
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Affiliation(s)
- Saber Imani
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, China
| | | | - Ali Babaeizad
- Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
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2
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Furriel F, Ferreira H, Sampaio-Ribeiro G, Pereira M, Eloy C, Neves B, Paiva A, Parada B, Gomes C. Co-targeting the CD73-adenosinergic axis enhances the anti-tumor efficacy of anti-PD-L1 immunotherapy in bladder cancer. Biomed Pharmacother 2025; 188:118188. [PMID: 40424822 DOI: 10.1016/j.biopha.2025.118188] [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: 02/26/2025] [Revised: 05/07/2025] [Accepted: 05/21/2025] [Indexed: 05/29/2025] Open
Abstract
Immune checkpoint inhibitors have significantly improved advanced bladder cancer care, but resistance remains a significant challenge. Adenosinergic signaling is an immunosuppressive mechanism hindered by tumor cells to escape from immune surveillance and suppress antitumor immune responses. Herein, we investigate whether co-targeting the adenosine pathway can modulate tumor immunity and enhance the efficacy of anti-PD-L1 therapy in an orthotopic murine bladder cancer model. We observed higher expression of the ectonucleotidases CD39 and CD73 in tumor cells and CD4+ and CD8+ T cells within the tumor microenvironment and peripheral circulation and upregulation of the adenosine receptors A2A and A2B in tumor cells, further confirming the activation of the adenosinergic pathway in this murine model. CD39 inhibition demonstrated no therapeutic benefits nor synergistic effect with anti-PD-L1 immunotherapy in tumor-bearing mice. On the contrary, CD73 inhibition reduced tumor progression and synergized with anti-PD-L1, leading to complete remission in 38 % of cases and a significant reduction in tumor mass in the remainder compared to anti-PD-L1 monotherapy. This combination resulted in favorable systemic immune modulation, including increased circulating CD4+ and CD8+ T cells and a decreased neutrophil-to-lymphocyte ratio. These findings suggest that the adenosinergic pathway limits the efficacy of anti-PD-L1 immunotherapy in invasive bladder cancer. Targeting the CD73 adenosinergic axis may enhance its effectiveness, offering a promising strategy to overcome resistance.
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Affiliation(s)
- Frederico Furriel
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Department of Urology, Unidade Local de Saúde da Região de Leiria, Leiria 2410-197, Portugal
| | - Hugo Ferreira
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Gabriela Sampaio-Ribeiro
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Margarida Pereira
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Catarina Eloy
- Pathology Department, Medical Faculty of University of Porto, Porto 4200-319, Portugal; Pathology Laboratory, Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Porto 4200-135, Portugal
| | - Beatriz Neves
- Pathology Laboratory, Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Porto 4200-135, Portugal
| | - Artur Paiva
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Flow Cytometry Unit, Clinical Pathology Department, Unidade Local de Saúde de Coimbra, Coimbra 3000-075, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Coimbra 3046-854, Portugal
| | - Belmiro Parada
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Department of Urology and Renal Transplantation, Unidade Local de Saúde de Coimbra, Coimbra 3000-075, Portugal
| | - Célia Gomes
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
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Dehghan F, Metanat Y, Askarizadeh M, Ahmadi E, Moradi V. Novel gene manipulation approaches to unlock the existing bottlenecks of CAR-NK cell therapy. Front Cell Dev Biol 2025; 12:1511931. [PMID: 40007761 PMCID: PMC11850336 DOI: 10.3389/fcell.2024.1511931] [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: 10/15/2024] [Accepted: 12/10/2024] [Indexed: 02/27/2025] Open
Abstract
Currently, CAR-T cell therapy is known as an efficacious treatment for patients with relapsed/refractory hematologic malignancies. Nonetheless, this method faces several bottlenecks, including low efficacy for solid tumors, lethal adverse effects, high cost of autologous products, and the risk of GvHD in allogeneic settings. As a potential alternative, CAR-NK cell therapy can overcome most of the limitations of CAR-T cell therapy and provide an off-the-shelf, safer, and more affordable product. Although published results from preclinical and clinical studies with CAR-NK cells are promising, several bottlenecks must be unlocked to maximize the effectiveness of CAR-NK cell therapy. These bottlenecks include low in vivo persistence, low trafficking into tumor sites, modest efficacy in solid tumors, and sensitivity to immunosuppressive tumor microenvironment. In recent years, advances in gene manipulation tools and strategies have laid the groundwork to overcome the current bottlenecks of CAR-NK cell therapy. This review will introduce the existing gene manipulation tools and discuss their advantages and disadvantages. We will also explore how these tools can enhance CAR-NK cell therapy's safety and efficacy.
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Affiliation(s)
- Fatemeh Dehghan
- Department of Anatomy and Molecular Biology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Yekta Metanat
- Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Sistan and Baluchestan Province, Iran
| | - Mandana Askarizadeh
- School of Biology and Ecology, University of Maine, Orono, ME, United States
| | - Ehsan Ahmadi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Moradi
- Department of Hematology and Blood Transfusion Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Ma M, Zhang Y, Pu K, Tang W. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity. Chem Soc Rev 2025; 54:653-714. [PMID: 39620588 DOI: 10.1039/d4cs00679h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
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Affiliation(s)
- Muye Ma
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Dr 2, Singapore, 117545, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore, 117597, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Wei Tang
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- Department of Pharmacy and Pharmaceutic Sciences, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore
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Chen X, Agustinus AS, Li J, DiBona M, Bakhoum SF. Chromosomal instability as a driver of cancer progression. Nat Rev Genet 2025; 26:31-46. [PMID: 39075192 DOI: 10.1038/s41576-024-00761-7] [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] [Accepted: 06/25/2024] [Indexed: 07/31/2024]
Abstract
Chromosomal instability (CIN) refers to an increased propensity of cells to acquire structural and numerical chromosomal abnormalities during cell division, which contributes to tumour genetic heterogeneity. CIN has long been recognized as a hallmark of cancer, and evidence over the past decade has strongly linked CIN to tumour evolution, metastasis, immune evasion and treatment resistance. Until recently, the mechanisms by which CIN propels cancer progression have remained elusive. Beyond the generation of genomic copy number heterogeneity, recent work has unveiled additional tumour-promoting consequences of abnormal chromosome segregation. These mechanisms include complex chromosomal rearrangements, epigenetic reprogramming and the induction of cancer cell-intrinsic inflammation, emphasizing the multifaceted role of CIN in cancer.
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Affiliation(s)
- Xuelan Chen
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Albert S Agustinus
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Pharmacology Graduate Program, Weill Cornell Medicine, New York, NY, USA
| | - Jun Li
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melody DiBona
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samuel F Bakhoum
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Simões JLB, Braga GDC, Fontana M, Assmann CE, Bagatini MD. The Neuroprotective Role of A2A Adenosine Purinoceptor Modulation as a Strategy Against Glioblastoma. Brain Sci 2024; 14:1286. [PMID: 39766485 PMCID: PMC11674974 DOI: 10.3390/brainsci14121286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Glioblastoma (GBM) is a highly lethal type of cancer, frequently presenting an unfavorable prognosis. The current treatment options for this neoplasia are still limited, highlighting the need for further research evaluating new drugs to treat GBM or to serve as an adjuvant to improve the efficiency of currently used therapies. In this sense, the inhibition of A2A receptors in the brain has presented a neuroprotective role for several diseases, such as neurodegenerative conditions, and it has been suggested as a possible pharmacological target in some types of cancer; thus, it also can be underscored as a potential target in GBM. Recently, Istradefylline (IST) was approved by the FDA for treating Parkinson's disease, representing a safe drug that acts through the inhibition of the A2A receptor, and it has also been suggested as an antineoplastic drug. Therefore, this work aims to explore the effects of A2A receptor inhibition as a therapy for GBM and assess the feasibility of this blockage occurring through the effects of IST.
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Affiliation(s)
- Júlia Leão Batista Simões
- Medical School, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil; (J.L.B.S.); (G.d.C.B.); (M.F.)
| | - Geórgia de Carvalho Braga
- Medical School, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil; (J.L.B.S.); (G.d.C.B.); (M.F.)
| | - Michelli Fontana
- Medical School, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil; (J.L.B.S.); (G.d.C.B.); (M.F.)
| | - Charles Elias Assmann
- Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria 97105-900, RS, Brazil
| | - Margarete Dulce Bagatini
- Graduate Program in Medical Sciences, Federal University of Fronteira Sul, Chapecó 89815-899, SC, Brazil
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Di Virgilio F, Vultaggio-Poma V, Tarantini M, Giuliani AL. Overview of the role of purinergic signaling and insights into its role in cancer therapy. Pharmacol Ther 2024; 262:108700. [PMID: 39111410 DOI: 10.1016/j.pharmthera.2024.108700] [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: 01/07/2024] [Revised: 07/05/2024] [Accepted: 07/31/2024] [Indexed: 08/30/2024]
Abstract
Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer. This is supporting the novel concept of "purinergic immune checkpoint" (PIC) in cancer therapy. In the present review we will address a) the basic pharmacology and cell biology of the purinergic system; b) principles of its pathophysiology in human diseases; c) implications for cell death, cell proliferation and cancer; d) novel molecular tools to investigate nucleotide homeostasis in the extracellular environment; e) recent developments in the pharmacology of P1, P2 receptors and related ecto-enzymes; f) P1 and P2 ligands as novel diagnostic tools; g) current issues in PIC-based anti-cancer therapy. This review will provide an appraisal of the current status of purinergic signaling in cancer and will help identify future avenues of development.
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Affiliation(s)
| | | | - Mario Tarantini
- Department of Medical Sciences, University of Ferrara, Italy
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Venugopala KN, Buccioni M. Current Understanding of the Role of Adenosine Receptors in Cancer. Molecules 2024; 29:3501. [PMID: 39124905 PMCID: PMC11313767 DOI: 10.3390/molecules29153501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/21/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Cancer, a complex array of diseases, involves the unbridled proliferation and dissemination of aberrant cells in the body, forming tumors that can infiltrate neighboring tissues and metastasize to distant sites. With over 200 types, each cancer has unique attributes, risks, and treatment avenues. Therapeutic options encompass surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, targeted therapy, or a blend of these methods. Yet, these treatments face challenges like late-stage diagnoses, tumor diversity, severe side effects, drug resistance, targeted drug delivery hurdles, and cost barriers. Despite these hurdles, advancements in cancer research, encompassing biology, genetics, and treatment, have enhanced early detection methods, treatment options, and survival rates. Adenosine receptors (ARs), including A1, A2A, A2B, and A3 subtypes, exhibit diverse roles in cancer progression, sometimes promoting or inhibiting tumor growth depending on the receptor subtype, cancer type, and tumor microenvironment. Research on AR ligands has revealed promising anticancer effects in lab studies and animal models, hinting at their potential as cancer therapeutics. Understanding the intricate signaling pathways and interactions of adenosine receptors in cancer is pivotal for crafting targeted therapies that optimize benefits while mitigating drawbacks. This review delves into each adenosine receptor subtype's distinct roles and signaling pathways in cancer, shedding light on their potential as targets for improving cancer treatment outcomes.
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Affiliation(s)
- Katharigatta Narayanaswamy Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Michela Buccioni
- School of Pharmacy, Medicinal Chemistry Unit, ChIP, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy;
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Spiga M, Martini E, Maffia MC, Ciceri F, Ruggiero E, Potenza A, Bonini C. Harnessing the tumor microenvironment to boost adoptive T cell therapy with engineered lymphocytes for solid tumors. Semin Immunopathol 2024; 46:8. [PMID: 39060547 DOI: 10.1007/s00281-024-01011-y] [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: 12/04/2023] [Accepted: 03/18/2024] [Indexed: 07/28/2024]
Abstract
Adoptive cell therapy (ACT) using Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) engineered T cells represents an innovative therapeutic approach for the treatment of hematological malignancies, yet its application for solid tumors is still suboptimal. The tumor microenvironment (TME) places several challenges to overcome for a satisfactory therapeutic effect, such as physical barriers (fibrotic capsule and stroma), and inhibitory signals impeding T cell function. Some of these obstacles can be faced by combining ACT with other anti-tumor approaches, such as chemo/radiotherapy and checkpoint inhibitors. On the other hand, cutting edge technological tools offer the opportunity to overcome and, in some cases, take advantage of TME intrinsic characteristics to boost ACT efficacy. These include: the exploitation of chemokine gradients and integrin expression for preferential T-cell homing and extravasation; metabolic changes that have direct or indirect effects on TCR-T and CAR-T cells by increasing antigen presentation and reshaping T cell phenotype; introduction of additional synthetic receptors on TCR-T and CAR-T cells with the aim of increasing T cells survival and fitness.
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Affiliation(s)
- Martina Spiga
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elisa Martini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Chiara Maffia
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabio Ciceri
- Vita-Salute San Raffaele University, Milan, Italy
- Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Eliana Ruggiero
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessia Potenza
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Chiara Bonini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
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Farhangnia P, Khorramdelazad H, Nickho H, Delbandi AA. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol 2024; 17:40. [PMID: 38835055 PMCID: PMC11151541 DOI: 10.1186/s13045-024-01561-6] [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: 04/09/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
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Affiliation(s)
- Pooya Farhangnia
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Nickho
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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11
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Zhu C, Wu Q, Sheng T, Shi J, Shen X, Yu J, Du Y, Sun J, Liang T, He K, Ding Y, Li H, Gu Z, Wang W. Rationally designed approaches to augment CAR-T therapy for solid tumor treatment. Bioact Mater 2024; 33:377-395. [PMID: 38059121 PMCID: PMC10696433 DOI: 10.1016/j.bioactmat.2023.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/05/2023] [Accepted: 11/06/2023] [Indexed: 12/08/2023] Open
Abstract
Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells' insufficient infiltration and rapid dysfunction. The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences. In addition, CAR-T therapy also raises safety concerns, including potential cytokine release storm, on-target/off-tumor toxicities, and neuro-system side effects. Here we comprehensively review various targeting aspects, including CAR-T cell design, tumor modulation, and delivery strategy. We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells, directly manipulating tumor tissue microenvironments, and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.
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Affiliation(s)
- Chaojie Zhu
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Qing Wu
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Tao Sheng
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Jiaqi Shi
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Xinyuan Shen
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Jicheng Yu
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yang Du
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jie Sun
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
- Department of Cell Biology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Tingxizi Liang
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Kaixin He
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, 310009, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, 310058, China
| | - Hongjun Li
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Zhen Gu
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
- Jinhua Institute of Zhejiang University, Jinhua, 321299, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, 310009, China
- ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, 310058, China
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12
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Bhise K, Gavande NS, Iyer AK. Leveraging hypoxia in triple-negative breast cancer as a promising treatment strategy. Drug Discov Today 2023; 28:103761. [PMID: 37660983 DOI: 10.1016/j.drudis.2023.103761] [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: 05/11/2023] [Revised: 08/08/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
Current treatment strategies for triple-negative breast cancer (TNBC) are based upon conventional chemotherapy, immunotherapy, or a combination of both. The treatment regimen for chemotherapy is often a combination of two or more drugs, either dose dense or low dose for synergy. Anthracyclines, alkylating agents, antimicrotubule agents, and antimetabolites for early-stage TNBC; and antimetabolites, non-taxane microtubule inhibitors, and cross-linker platinums for late-stage TNBC are usually administered in the clinical setting. Newer options for patients with advanced TNBC, such as poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, have recently emerged for cases where surgery is not a viable option and the disease has metastasized. This review outlines the current trends in hypoxia-inspired treatment strategies for TNBC with a focus on clinical trials.
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Affiliation(s)
- Ketki Bhise
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA
| | - Navnath S Gavande
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, USA
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Imaging Program, Karmanos Cancer Institute, Detroit, MI, USA.
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13
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Todd KL, Lai J, Sek K, Huang YK, Newman DM, Derrick EB, Koay HF, Nguyen D, Hoang TX, Petley EV, Chan CW, Munoz I, House IG, Lee JN, Kim JS, Li J, Tong J, N de Menezes M, Scheffler CM, Yap KM, Chen AXY, Dunbar PA, Haugen B, Parish IA, Johnstone RW, Darcy PK, Beavis PA. A 2AR eGFP reporter mouse enables elucidation of A 2AR expression dynamics during anti-tumor immune responses. Nat Commun 2023; 14:6990. [PMID: 37914685 PMCID: PMC10620403 DOI: 10.1038/s41467-023-42734-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 10/20/2023] [Indexed: 11/03/2023] Open
Abstract
There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A2AR receptor. Understanding of the mechanism by which A2AR is regulated has been hindered by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A2AR eGFP reporter mouse is developed, enabling the expression of A2AR during ongoing anti-tumor immune responses to be assessed. This reveals that A2AR is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4+ and CD8+ T lymphocytes and on a MHCIIhiCD86hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1+A2AR- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A2AR and synergizes with A2AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A2AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.
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Affiliation(s)
- Kirsten L Todd
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia.
| | - Junyun Lai
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Kevin Sek
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Yu-Kuan Huang
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Dane M Newman
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
- Translational Hematology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Emily B Derrick
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Hui-Fern Koay
- Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
| | - Dat Nguyen
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Thang X Hoang
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Emma V Petley
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Cheok Weng Chan
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Isabelle Munoz
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Imran G House
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Joel N Lee
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Joelle S Kim
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Jasmine Li
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Junming Tong
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Maria N de Menezes
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Christina M Scheffler
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Kah Min Yap
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Amanda X Y Chen
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Phoebe A Dunbar
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Brandon Haugen
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Ian A Parish
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Ricky W Johnstone
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
- Translational Hematology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Phillip K Darcy
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
- Department of Immunology, Monash University, Clayton, Australia
| | - Paul A Beavis
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia.
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14
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Chen L, Alabdullah M, Mahnke K. Adenosine, bridging chronic inflammation and tumor growth. Front Immunol 2023; 14:1258637. [PMID: 38022572 PMCID: PMC10643868 DOI: 10.3389/fimmu.2023.1258637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by "hijacking" CD39+/CD73+ cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.
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Affiliation(s)
| | | | - Karsten Mahnke
- Department of Dermatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany
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15
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Allard B, Jacoberger-Foissac C, Cousineau I, Bareche Y, Buisseret L, Chrobak P, Allard D, Pommey S, Ah-Pine F, Duquenne S, Picard F, Stagg J. Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma. Cell Rep Med 2023; 4:101188. [PMID: 37729873 PMCID: PMC10518627 DOI: 10.1016/j.xcrm.2023.101188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 06/22/2023] [Accepted: 08/15/2023] [Indexed: 09/22/2023]
Abstract
Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC.
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Affiliation(s)
- Bertrand Allard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - Célia Jacoberger-Foissac
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - Isabelle Cousineau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - Yacine Bareche
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | | | - Pavel Chrobak
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - David Allard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - Sandra Pommey
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada
| | - Franck Ah-Pine
- Department of Pathology, CHU Sud Réunion, Saint-Pierre, France
| | | | - Fabien Picard
- Montréal Heart Institute, Cardiology Department, Université de Montréal, Montreal, QC, Canada; Hopital Cochin, Cardiology Department, Université de Paris, Paris, France
| | - John Stagg
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada.
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16
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Kutryb-Zając B, Kawecka A, Nasadiuk K, Braczko A, Stawarska K, Caiazzo E, Koszałka P, Cicala C. Drugs targeting adenosine signaling pathways: A current view. Biomed Pharmacother 2023; 165:115184. [PMID: 37506580 DOI: 10.1016/j.biopha.2023.115184] [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: 05/18/2023] [Revised: 07/06/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.
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Affiliation(s)
- Barbara Kutryb-Zając
- Department of Biochemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland.
| | - Ada Kawecka
- Department of Biochemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland
| | - Khrystyna Nasadiuk
- Department of Biochemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland
| | - Alicja Braczko
- Department of Biochemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland
| | - Klaudia Stawarska
- Department of Biochemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland
| | - Elisabetta Caiazzo
- Department of Pharmacy, School of Medicine, University of Naple Federico II, 80131 Naples, Italy
| | - Patrycja Koszałka
- Laboratory of Cell Biology and Immunology, Institute of Medical Biotechnology and Experimental Oncology, Intercollegiate Faculty of Biotechnology University of Gdańsk and Medical University of Gdańsk, Medical University of Gdańsk, 80-211 Gdańsk, Poland
| | - Carla Cicala
- Department of Pharmacy, School of Medicine, University of Naple Federico II, 80131 Naples, Italy
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17
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Stagg J, Golden E, Wennerberg E, Demaria S. The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy. Sci Immunol 2023; 8:eabq3015. [PMID: 37418547 PMCID: PMC10394739 DOI: 10.1126/sciimmunol.abq3015] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/14/2023] [Indexed: 07/09/2023]
Abstract
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
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Affiliation(s)
- John Stagg
- Centre de Recherche du Centre Hospitalier de
l’Université de Montréal, 900 St-Denis street, Montreal,
Quebec, Canada, H2X 0A9
| | - Encouse Golden
- Department of Radiation Oncology, Weill Cornell Medicine,
New York, NY 10065, USA
| | - Erik Wennerberg
- Division of Radiotherapy and Imaging, Institute of Cancer
Research, London SM2 5NG, UK
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine,
New York, NY 10065, USA
- Department of Pathology and Laboratory Medicine, Weill
Cornell Medicine, New York, NY, 10065, USA
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18
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Sharon S, Daher-Ghanem N, Zaid D, Gough MJ, Kravchenko-Balasha N. The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer. FRONTIERS IN ORAL HEALTH 2023; 4:1180869. [PMID: 37496754 PMCID: PMC10366623 DOI: 10.3389/froh.2023.1180869] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/27/2023] [Indexed: 07/28/2023] Open
Abstract
Although treatment modalities for head and neck cancer have evolved considerably over the past decades, survival rates have plateaued. The treatment options remained limited to definitive surgery, surgery followed by fractionated radiotherapy with optional chemotherapy, and a definitive combination of fractionated radiotherapy and chemotherapy. Lately, immunotherapy has been introduced as the fourth modality of treatment, mainly administered as a single checkpoint inhibitor for recurrent or metastatic disease. While other regimens and combinations of immunotherapy and targeted therapy are being tested in clinical trials, adapting the appropriate regimens to patients and predicting their outcomes have yet to reach the clinical setting. Radiotherapy is mainly regarded as a means to target cancer cells while minimizing the unwanted peripheral effect. Radiotherapy regimens and fractionation are designed to serve this purpose, while the systemic effect of radiation on the immune response is rarely considered a factor while designing treatment. To bridge this gap, this review will highlight the effect of radiotherapy on the tumor microenvironment locally, and the immune response systemically. We will review the methodology to identify potential targets for therapy in the tumor microenvironment and the scientific basis for combining targeted therapy and radiotherapy. We will describe a current experience in preclinical models to test these combinations and propose how challenges in this realm may be faced. We will review new players in targeted therapy and their utilization to drive immunogenic response against head and neck cancer. We will outline the factors contributing to head and neck cancer heterogeneity and their effect on the response to radiotherapy. We will review in-silico methods to decipher intertumoral and intratumoral heterogeneity and how these algorithms can predict treatment outcomes. We propose that (a) the sequence of surgery, radiotherapy, chemotherapy, and targeted therapy should be designed not only to annul cancer directly, but to prime the immune response. (b) Fractionation of radiotherapy and the extent of the irradiated field should facilitate systemic immunity to develop. (c) New players in targeted therapy should be evaluated in translational studies toward clinical trials. (d) Head and neck cancer treatment should be personalized according to patients and tumor-specific factors.
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Affiliation(s)
- Shay Sharon
- Department of Oral and Maxillofacial Surgery, Hadassah Medical Center, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Oral and Maxillofacial Surgery, Boston University and Boston Medical Center, Boston, MA, United States
| | - Narmeen Daher-Ghanem
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Deema Zaid
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Michael J. Gough
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Nataly Kravchenko-Balasha
- The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem, Israel
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19
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Kurago Z, Guo G, Shi H, Bollag RJ, Groves MW, Byrd JK, Cui Y. Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy. Front Immunol 2023; 14:1212209. [PMID: 37435071 PMCID: PMC10330720 DOI: 10.3389/fimmu.2023.1212209] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/31/2023] [Indexed: 07/13/2023] Open
Abstract
The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.
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Affiliation(s)
- Zoya Kurago
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia at Augusta University, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Gang Guo
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Huidong Shi
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Roni J. Bollag
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Michael W. Groves
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - J. Kenneth Byrd
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Yan Cui
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
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20
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Zahavi D, Hodge JW. Targeting Immunosuppressive Adenosine Signaling: A Review of Potential Immunotherapy Combination Strategies. Int J Mol Sci 2023; 24:ijms24108871. [PMID: 37240219 DOI: 10.3390/ijms24108871] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable clinical success, resistance is common, and there is an urgent need to identify additional targets. Extracellular adenosine, a metabolite of ATP, is found at high levels in the tumor microenvironment and has potent immunosuppressive properties. Targeting members of the adenosine signaling pathway represents a promising immunotherapeutic modality that can potentially synergize with conventional anti-cancer treatment strategies. In this review, we discuss the role of adenosine in cancer, present preclinical and clinical data on the efficacy adenosine pathway inhibition, and discuss possible combinatorial approaches.
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Affiliation(s)
- David Zahavi
- Center for Immuno-Oncology (CIO), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm 8B13, 9000 Rockville Pike, Bethesda, MD 20879, USA
| | - James W Hodge
- Center for Immuno-Oncology (CIO), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm 8B13, 9000 Rockville Pike, Bethesda, MD 20879, USA
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21
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Thiery J. Modulation of the antitumor immune response by cancer-associated fibroblasts: mechanisms and targeting strategies to hamper their immunosuppressive functions. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:598-629. [PMID: 36338519 PMCID: PMC9630350 DOI: 10.37349/etat.2022.00103] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are highly heterogeneous players that shape the tumor microenvironment and influence tumor progression, metastasis formation, and response to conventional therapies. During the past years, some CAFs subsets have also been involved in the modulation of immune cell functions, affecting the efficacy of both innate and adaptive anti-tumor immune responses. Consequently, the implication of these stromal cells in the response to immunotherapeutic strategies raised major concerns. In this review, current knowledge of CAFs origins and heterogeneity in the tumor stroma, as well as their effects on several immune cell populations that explain their immunosuppressive capabilities are summarized. The current development of therapeutic strategies for targeting this population and their implication in the field of cancer immunotherapy is also highlighted.
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Affiliation(s)
- Jerome Thiery
- INSERM, UMR 1186, 94800 Villejuif, France
- Gustave Roussy Cancer Campus, 94805 Villejuif, France
- University Paris Saclay, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France
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22
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Hamoud AR, Bach K, Kakrecha O, Henkel N, Wu X, McCullumsmith RE, O’Donovan SM. Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment? Int J Mol Sci 2022; 23:ijms231911835. [PMID: 36233136 PMCID: PMC9570456 DOI: 10.3390/ijms231911835] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/23/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.
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Affiliation(s)
- Abdul-Rizaq Hamoud
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Karen Bach
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Ojal Kakrecha
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Nicholas Henkel
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Xiaojun Wu
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Robert E. McCullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
- Neurosciences Institute, ProMedica, Toledo, OH 43606, USA
| | - Sinead M. O’Donovan
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
- Correspondence:
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23
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Skorupan N, Palestino Dominguez M, Ricci SL, Alewine C. Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:4209. [PMID: 36077755 PMCID: PMC9454553 DOI: 10.3390/cancers14174209] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 12/04/2022] Open
Abstract
Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.
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Affiliation(s)
- Nebojsa Skorupan
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Medical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mayrel Palestino Dominguez
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Samuel L. Ricci
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Christine Alewine
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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24
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Bova V, Filippone A, Casili G, Lanza M, Campolo M, Capra AP, Repici A, Crupi L, Motta G, Colarossi C, Chisari G, Cuzzocrea S, Esposito E, Paterniti I. Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness. Cancers (Basel) 2022; 14:cancers14164032. [PMID: 36011024 PMCID: PMC9406358 DOI: 10.3390/cancers14164032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Given the rising mortality rate caused by GBM, current therapies do not appear to be effective in counteracting tumor progression. The role of adenosine and its interaction with specific receptor subtypes in various physiological functions has been studied for years. Only recently, adenosine has been defined as a tumor-protective target because of its accumulation in the tumor microenvironment. Current knowledge of the adenosine pathway and its involvement in brain tumors would support research in the development of adenosine receptor antagonists that could represent alternative treatments for glioblastoma, used either alone and/or in combination with chemotherapy, immunotherapy, or both. Abstract Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.
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Affiliation(s)
- Valentina Bova
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Alessia Filippone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Marika Lanza
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Alberto Repici
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Lelio Crupi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Gianmarco Motta
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Cristina Colarossi
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Giulia Chisari
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
- Correspondence: ; Tel.: +39-090-676-5208
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
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25
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[Blocking Adenosine/A2AR Pathway for Cancer Therapy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:460-467. [PMID: 35899442 PMCID: PMC9346148 DOI: 10.3779/j.issn.1009-3419.2022.102.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies.
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26
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Guo S, Han F, Zhu W. CD39 - A bright target for cancer immunotherapy. Biomed Pharmacother 2022; 151:113066. [PMID: 35550530 DOI: 10.1016/j.biopha.2022.113066] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 11/27/2022] Open
Abstract
The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumor microenvironment, and cancer immune evasion largely involves the generation of high amounts of immunosuppressive extracellular adenosine (eADO). Consequently, inhibition of eADO-generating enzymes and/or eADO receptors can effectively restore the antitumor immunity of multiple immune cells. With several clinical strategies currently being explored to modulating the eADO pathway in patients with cancer, recent clinical data with antagonists targeting CD73 and A2A receptor have demonstrated a promising therapeutic potential in cancer. Recent findings reveal that the ectonucleotidase CD39, the limiting enzyme been viewed as "immunological switch", converts ATP-driven pro-inflammatory milieu to an anti-inflammatory state mediated by adenosine. Owing to its superior feature of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of extracellular ATP to restore antitumor immunity, several inhibitors and clinical trials based on CD39 are being evaluated. Consequently, there is currently a focus on understanding the role of CD39 in governing immunity and how therapeutic strategies targeting this pathway alter the antitumor potential. We herein review the impact of CD39 on tumor microenvironment with a focus on treatment preference. Additionally, we also discuss the implication for rational combination therapies, molecular regulation, as well as potential limitations.
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Affiliation(s)
- Shuwei Guo
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fengfeng Han
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
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27
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Liu S, Ding W, Huang W, Zhang Z, Guo Y, Zhang Q, Wu L, Li Y, Qin R, Li J, Shi T, Zhang X, Lei J, Hu W. Discovery of Novel Benzo[4,5]imidazo[1,2- a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A 2A Adenosine Receptor Antagonists. J Med Chem 2022; 65:8933-8947. [PMID: 35714367 DOI: 10.1021/acs.jmedchem.2c00101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The blockade of A2A adenosine receptor (A2AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, A2AAR has been proposed as a promising target for cancer immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-a]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist in vivo. The structure-activity relationship studies were performed by molecular modeling and radioactive assay. The in vitro anticancer activities were evaluated by 3',5'-cyclic adenosine monophosphate (cAMP) functional and T cell activation assay. The most potent compound 12o·2HCl showed much higher affinity toward A2AAR (Ki = 0.08 nM) and exhibited more significant in vitro immunostimulatory anticancer activity than clinical antagonist AZD4635. More importantly, 12o·2HCl significantly inhibited the growth of triple-negative breast cancer by reversing immunosuppressive tumor microenvironment in the xenograft mouse model without severe toxicity at the testing dose. These results make 12o·2HCl a promising immunotherapy anticancer drug candidate.
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Affiliation(s)
- Shuhao Liu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Wen Ding
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Weifeng Huang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Zhijing Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Yinfeng Guo
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Qiyi Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.,National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Linna Wu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Yukai Li
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Rui Qin
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Jiahao Li
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Taoda Shi
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Xiaolei Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.,National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Jinping Lei
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Wenhao Hu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
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28
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Augustin RC, Leone RD, Naing A, Fong L, Bao R, Luke JJ. Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy. J Immunother Cancer 2022; 10:jitc-2021-004089. [PMID: 35135866 PMCID: PMC8830302 DOI: 10.1136/jitc-2021-004089] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/20/2022] Open
Abstract
Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
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Affiliation(s)
- Ryan C Augustin
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Robert D Leone
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lawrence Fong
- Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA
| | - Riyue Bao
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Jason J Luke
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA .,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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29
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Karoon Kiani F, Izadi S, Ansari Dezfouli E, Ebrahimi F, Mohammadi M, Chalajour H, Mortazavi Bulus M, Nasr Esfahani M, Karpisheh V, Mahmoud Salehi Khesht A, Abbaszadeh-Goudarzi K, Soleimani A, Gholizadeh Navashenaq J, Ahmadi M, Hassannia H, Hojjat-Farsangi M, Shahmohammadi Farid S, Hashemi V, Jadidi-Niaragh F. Simultaneous silencing of the A2aR and PD-1 immune checkpoints by siRNA-loaded nanoparticles enhances the immunotherapeutic potential of dendritic cell vaccine in tumor experimental models. Life Sci 2022; 288:120166. [PMID: 34813798 DOI: 10.1016/j.lfs.2021.120166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/10/2021] [Accepted: 11/17/2021] [Indexed: 12/20/2022]
Abstract
Following various immunotherapies, lack of proper anti-tumor immune responses is considered a significant problem in novel cancer therapeutic approaches. The expression of inhibitory checkpoint molecules on tumor-infiltrating T cells is one of the main reasons for the ineffectiveness of various immunotherapies. Therefore, we decided to inhibit two of the most important immune checkpoints expressed on tumor-associated T cells, PD-1 and A2aR. Ligation of PD-1 with PD-L1 and A2aR with adenosine significantly suppress T cell responses against tumor cells. Whitin tumors, specific inhibition of these molecules on T cells is of particular importance for successful immunotherapy as well as the elimination of treatment-associated side-effects. Thus, in this study, superparamagnetic iron oxide (SPION) nanoparticles (NPs) were covered by chitosan lactate (CL), functionalized with TAT peptide, and loaded with siRNA molecules against PD-1 and A2aR. Appropriate physicochemical properties of the prepared NPs resulted in efficient delivery of siRNA to tumor-derived T cells and suppressed the expression of A2aR and PD-1, ex vivo. T cell functions such as cytokine secretion and proliferation were considerably enhanced by the downregulation of these molecules which led to an increase in their survival time. Interestingly, treatment of CT26 and 4T1 mouse tumors with siRNA-loaded NPs not only inhibited tumor growth but also markedly increased anti-tumor immune responses and survival time. The results strongly support the efficacy of SPION-CL-TAT NPs loaded with anti-PD-1/A2aR siRNAs in cancer therapy and their further development for cancer patients in the near future.
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Affiliation(s)
- Fariba Karoon Kiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Izadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ehsan Ansari Dezfouli
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Farbod Ebrahimi
- Nanoparticle Process Technology, Faculty of Engineering, University of Duisburg-Essen, Duisburg, Germany
| | - Mohammad Mohammadi
- Department of Cell and Molecular Biology, School of Advanced Sciences, Islamic Azad University, Tehran, Medical Branch, Iran
| | - Hengameh Chalajour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Vahid Karpisheh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armin Mahmoud Salehi Khesht
- Department of Biochemistry, Faculty of Materials Engineering, Islamic Azad University, Najafabad Branch, Najafabad, Iran
| | | | - Ali Soleimani
- Department of Public Health, Maragheh University of Medical Sciences, Maragheh, Iran
| | | | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Hassannia
- Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; Department of Immunology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | | | - Vida Hashemi
- Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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30
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Wang P, Tang L, Zhou B, Cheng L, Zhao RC, Zhang J. Analytical methods for the detection of PD-1/PD-L1 and other molecules related to immune checkpoints. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2021.116505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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31
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Liu G, Zhang Q, Liu G, Li D, Zhang L, Gu Z, Tian H, Zhang Y, Tian X. Disruption of adenosine 2A receptor improves the anti-tumor function of anti-mesothelin CAR T cells both in vitro and in vivo. Exp Cell Res 2021; 409:112886. [PMID: 34673000 DOI: 10.1016/j.yexcr.2021.112886] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 12/30/2022]
Abstract
Chimeric antigen receptor (CAR) T cells have been successfully used for the treatment of hematological malignancies including acute and chronic lymphoblastic leukemia. However, results of CAR T cell projects in solid tumors have been less impressive to date, partly because of immunosuppressive tumor microenvironment (TME). It is widely known that high adenosine production is an important factor causing tumor-induced immunosuppression in TME, and adenosine mediates the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Previous studies have shown that adenosine generated by cancer cells significantly inhibits T cell anti-tumor activity through binding and then activating adenosine 2A receptors (A2aRs) of T cells. Based on the previous work, in our study, we evaluated whether A2aR disruption by shRNA could enhance the anti-tumor function of anti-mesothelin (MSLN) CAR T cells both in vitro and in vivo. For this goal above, we used MSLN-positive human ovarian serous carcinoma cells (SKOV3) and human colon cancer cells (HCT116) as target cancer cells while MSLN-negative human ovarian cancer cells (ES2) as non-target cancer cells. We observed that targeting cell-intrinsic A2aR through shRNA overexpression caused significant A2aR disruption in CAR T cells and profoundly increased CAR T cell efficacy in both CAR T cell cytokine production and cytotoxicity towards MSLN-positive cancer cells in vitro. More importantly, in SKOV3 xenograft mouse models, anti-MSLN CAR-T cells significantly reduced the tumor burden compared with non-transduced T cells, and the anti-tumor activity of A2aR-disrupted anti-MSLN CAR-T cells was stronger than that of wild-type anti-MSLN CAR-T cells. Altogether, our study showed enhanced anti-tumor efficacy caused by shRNA-mediated A2aR disruption in anti-MSLN CAR T cells both in vitro and in vivo, which proved that shRNA-mediated modification of gene expression might be an excellent strategy for improving CAR T cell function in immunosuppressive tumor microenvironment (TME) and could potentially improve the outcome of treatment in clinical trials.
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Affiliation(s)
- Guodi Liu
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Qian Zhang
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Guoping Liu
- Department of General Surgery, Changhai Hospital, Shanghai, 200433, China
| | - Dehua Li
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Linsong Zhang
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Zhangjie Gu
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Huixin Tian
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China
| | - Yong Zhang
- Department of Pathology, Tumor Hospital of China Medical University and Liao Ning Cancer Hospital and Institute, Shenyang, 110042, China.
| | - Xiaoli Tian
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231, China.
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32
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Aggarwal V, Tuli HS, Varol M, Tuorkey M, Sak K, Parashar NC, Barwal TS, Sharma U, Iqubal A, Parashar G, Jain A. NOTCH signaling: Journey of an evolutionarily conserved pathway in driving tumor progression and its modulation as a therapeutic target. Crit Rev Oncol Hematol 2021; 164:103403. [PMID: 34214610 DOI: 10.1016/j.critrevonc.2021.103403] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Notch signaling, an evolutionarily conserved signaling cascade, is critical for normal biological processes of cell differentiation, development, and homeostasis. Deregulation of the Notch signaling pathway has been associated with tumor progression. Thus, Notch presents as an interesting target for a variety of cancer subtypes and its signaling mechanisms have been actively explored from the therapeutic viewpoint. However, besides acting as an oncogene, Notch pathway can possess also tumor suppressive functions, being implicated in inhibition of cancer development. Given such interesting dual and dynamic role of Notch, in this review, we discuss how the evolutionarily conserved Notch signaling pathway drives hallmarks of tumor progression and how it could be targeted for a promising treatment and management of cancer. In addition, the up-to-date information on the inhibitors currently under clinical trials for Notch targets is presented along with how NOTCH inhibitors can be used in conjunction with established chemotherapy/radiotherapy regimes.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, USA.
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Mugla, TR48000, Turkey.
| | - Muobarak Tuorkey
- Division of Physiology, Zoology Department, Faculty of Science, Damanhour University, Damanhour, Egypt.
| | | | - Nidarshana Chaturvedi Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard (Deemed to be University), Delhi, India.
| | - Gaurav Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
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33
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Alfei F, Ho PC, Lo WL. DCision-making in tumors governs T cell anti-tumor immunity. Oncogene 2021; 40:5253-5261. [PMID: 34290401 PMCID: PMC8390370 DOI: 10.1038/s41388-021-01946-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023]
Abstract
The exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell-T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.
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Affiliation(s)
- Francesca Alfei
- Department of Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Ping-Chih Ho
- Department of Oncology, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland.
| | - Wan-Lin Lo
- Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT, USA.
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34
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Leone RD, Powell JD. Fueling the Revolution: Targeting Metabolism to Enhance Immunotherapy. Cancer Immunol Res 2021; 9:255-260. [PMID: 33648947 DOI: 10.1158/2326-6066.cir-20-0791] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The success of immune-checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies has established the remarkable capacity of the immune system to fight cancer. Over the past several years, it has become clear that immune cell responses to cancer are critically dependent upon metabolic programs that are specific to both immune cell type and function. Metabolic features of cancer cells and the tumor microenvironment impose constraints on immune cell metabolism that can favor immunosuppressive phenotypes and block antitumor responses. Advances in both preclinical and clinical studies have demonstrated that metabolic interventions can dramatically enhance the efficacy of immune-based therapies for cancer. As such, understanding the metabolic requirements of immune cells in the tumor microenvironment, as well as the limitations imposed therein, can have significant benefits for informing both current practice and future research in cancer immunotherapy.
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Affiliation(s)
- Robert D Leone
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jonathan D Powell
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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35
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Kepp O, Bezu L, Yamazaki T, Di Virgilio F, Smyth MJ, Kroemer G, Galluzzi L. ATP and cancer immunosurveillance. EMBO J 2021; 40:e108130. [PMID: 34121201 DOI: 10.15252/embj.2021108130] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/24/2021] [Accepted: 04/05/2021] [Indexed: 12/14/2022] Open
Abstract
While intracellular adenosine triphosphate (ATP) occupies a key position in the bioenergetic metabolism of all the cellular compartments that form the tumor microenvironment (TME), extracellular ATP operates as a potent signal transducer. The net effects of purinergic signaling on the biology of the TME depend not only on the specific receptors and cell types involved, but also on the activation status of cis- and trans-regulatory circuitries. As an additional layer of complexity, extracellular ATP is rapidly catabolized by ectonucleotidases, culminating in the accumulation of metabolites that mediate distinct biological effects. Here, we discuss the molecular and cellular mechanisms through which ATP and its degradation products influence cancer immunosurveillance, with a focus on therapeutically targetable circuitries.
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Affiliation(s)
- Oliver Kepp
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université de Paris, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Lucillia Bezu
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université de Paris, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | | | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Qld, Australia
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université de Paris, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.,Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,Department of Women's and Children's Health, Karolinska University Hospital, 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.,Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.,Université de Paris, Paris, France
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36
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Desbois M, Wang Y. Cancer-associated fibroblasts: Key players in shaping the tumor immune microenvironment. Immunol Rev 2021; 302:241-258. [PMID: 34075584 DOI: 10.1111/imr.12982] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/14/2021] [Accepted: 04/30/2021] [Indexed: 12/18/2022]
Abstract
Cancer immunotherapies have rapidly changed the therapeutic landscape for cancer. Nevertheless, most of the patients show innate or acquired resistance to these therapies. Studies conducted in recent years have highlighted an emerging role of cancer-associated fibroblasts (CAFs) in immune regulation that shapes the tumor immune microenvironment (TIME) and influences response to cancer immunotherapies. In this review, we outline recent advances in the understanding of phenotypic and functional heterogeneity of CAFs. We will focus on emerging roles of CAFs in shaping the TIME, especially under a framework of tumor immunity continuum, and discuss current and future CAF-targeting therapeutic strategies in particular in the context of optimizing the success of immunotherapies.
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Affiliation(s)
- Mélanie Desbois
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
| | - Yulei Wang
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
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37
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CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nat Commun 2021; 12:3236. [PMID: 34050151 PMCID: PMC8163771 DOI: 10.1038/s41467-021-23331-5] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 04/22/2021] [Indexed: 12/16/2022] Open
Abstract
Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.
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38
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Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications. Biomedicines 2021; 9:biomedicines9060607. [PMID: 34073463 PMCID: PMC8227307 DOI: 10.3390/biomedicines9060607] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.
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39
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Javadrashid D, Baghbanzadeh A, Hemmat N, Hajiasgharzadeh K, Nourbakhsh NS, Lotfi Z, Baradaran B. Envisioning the immune system to determine its role in pancreatic ductal adenocarcinoma: Culprit or victim? Immunol Lett 2021; 232:48-59. [PMID: 33647329 DOI: 10.1016/j.imlet.2021.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC.
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Affiliation(s)
- Darya Javadrashid
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ziba Lotfi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
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40
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Hatfield SM, Sitkovsky MV. Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy. J Clin Invest 2020; 130:5629-5637. [PMID: 32870821 PMCID: PMC7598059 DOI: 10.1172/jci137554] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hypoxia/HIF-1α- and extracellular adenosine/A2 adenosine receptor-mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine-rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α-driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element- and hypoxia response element-containing immunosuppressive gene products (e.g., TGF-β). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism-based approach to cancer immunotherapy described here.
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41
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Notch Pathway: A Journey from Notching Phenotypes to Cancer Immunotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1287:201-222. [PMID: 33034034 DOI: 10.1007/978-3-030-55031-8_13] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Notch is a key evolutionary conserved pathway, which has fascinated and engaged the work of investigators in an uncountable number of biological fields, from development of metazoans to immunotherapy for cancer. The study of Notch has greatly contributed to the understanding of cancer biology and a substantial effort has been spent in designing Notch-targeting therapies. Due to its broad involvement in cancer, targeting Notch would allow to virtually modulate any aspect of the disease. However, this means that Notch-based therapies must be highly specific to avoid off-target effects. This review will present the newest mechanistic and therapeutic advances in the Notch field and discuss the promises and challenges of this constantly evolving field.
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42
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Li N, Tang N, Cheng C, Hu T, Wei X, Han W, Wang H. Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway. Oncoimmunology 2020; 9:1824643. [PMID: 33457103 PMCID: PMC7781731 DOI: 10.1080/2162402x.2020.1824643] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CAR-T cells, its effect on human CAR-T cells has not been fully elucidated. In particular, there was no evaluation of the CAR-T cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CAR-T cells, and only A2AR was responsible for adenosine-induced impairment of CAR-T cell function. Disrupting A2AR gene in human CAR-T cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CAR-T cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knock-out CAR-T cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knock-out CAR-T cells have the potential of being an improved CAR-T cell therapy in treating solid tumors.
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Affiliation(s)
- Na Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Na Tang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Chen Cheng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Tao Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | | | - Weidong Han
- Department of Bio-therapeutic, Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China
| | - Haoyi Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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43
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Thompson EA, Powell JD. Inhibition of the Adenosine Pathway to Potentiate Cancer Immunotherapy: Potential for Combinatorial Approaches. Annu Rev Med 2020; 72:331-348. [PMID: 32903139 DOI: 10.1146/annurev-med-060619-023155] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer immunotherapy has revolutionized the way that we think about treating cancer. Although checkpoint blockade therapy, including anti-PD-1/PD-L1 and anti-CTLA-4, has shown remarkable success, the responses are limited to only a subset of patients. This discrepancy highlights the many overlapping avenues for immune evasion or suppression that can be employed by a tumor. One such mechanism of immunosuppression is adenosinergic signaling within the tumor microenvironment. We provide an overview of the current status of clinical trials targeting the adenosine pathway, including CD73, CD39, and adenosine receptors. Additionally, we highlight several avenues that may be explored to further potentiate responses in the clinic by combining adenosine-targeting agents to target multiple arms of the pathway or by using conventional immunotherapy agents.
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Affiliation(s)
- Elizabeth A Thompson
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; ,
| | - Jonathan D Powell
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; ,
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44
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Abstract
Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.
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Affiliation(s)
- Robert D Leone
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jonathan D Powell
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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45
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Sufficient numbers of anti-tumor T cells is a condition of maximal efficacy of anti-hypoxia-A2-adenosinergic drugs during cancer immunotherapy. Curr Opin Pharmacol 2020; 53:98-100. [PMID: 32861959 DOI: 10.1016/j.coph.2020.07.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 01/09/2023]
Abstract
The anti-hypoxia-A2-Adenosinergic immunotherapies of cancer emerged as the only available now approach to enable the tumor rejection in those progressing cancer patients that are refractory to all other current treatments. Several different classes of drugs are offered to inhibit the Hypoxia-HIF-1alpha-mediated and extracellular adenosine-A2A adenosine receptor-mediated immunosuppressive signaling in tumor microenvironment. It is suggested that the most promising treatments must include the blockade of cAMP-elevating A2A adenosine receptors and the elimination of hypoxia in tumors by oxygenation agents and hyperoxic breathing. The observations in ongoing clinical trials support this conclusion.
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Ng HHM, Lee RY, Goh S, Tay ISY, Lim X, Lee B, Chew V, Li H, Tan B, Lim S, Lim JCT, Au B, Loh JJH, Saraf S, Connolly JE, Loh T, Leow WQ, Lee JJX, Toh HC, Malavasi F, Lee SY, Chow P, Newell EW, Choo SP, Tai D, Yeong J, Lim TKH. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J Immunother Cancer 2020; 8:jitc-2020-000987. [PMID: 32847986 PMCID: PMC7451957 DOI: 10.1136/jitc-2020-000987] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC. Methods Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis. Results IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB. Conclusions A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.
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Affiliation(s)
- Harry Ho Man Ng
- Duke-NUS Medical School, Singapore.,Division of Pathology, Singapore General Hospital, Singapore
| | - Ren Yuan Lee
- Division of Pathology, Singapore General Hospital, Singapore.,Nanyang Technological University, Singapore
| | - Siting Goh
- Division of Pathology, Singapore General Hospital, Singapore
| | | | - Xinru Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Bernett Lee
- Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Valerie Chew
- Duke-NUS Medical School, Singapore.,SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore
| | - Huihua Li
- Division of Medicine, Singapore General Hospital, Singapore.,Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Benedict Tan
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Sherlly Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Jeffrey Chun Tatt Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Bijin Au
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | | | - Sahil Saraf
- Division of Pathology, Singapore General Hospital, Singapore
| | - John Edward Connolly
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Tracy Loh
- Division of Pathology, Singapore General Hospital, Singapore
| | - Wei Qiang Leow
- Division of Pathology, Singapore General Hospital, Singapore
| | | | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Fabio Malavasi
- Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Ser Yee Lee
- Duke-NUS Medical School, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Pierce Chow
- Duke-NUS Medical School, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Evan W Newell
- Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - David Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Joe Yeong
- Division of Pathology, Singapore General Hospital, Singapore .,Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore.,Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
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Sek K, Kats LM, Darcy PK, Beavis PA. Pharmacological and genetic strategies for targeting adenosine to enhance adoptive T cell therapy of cancer. Curr Opin Pharmacol 2020; 53:91-97. [PMID: 32854024 DOI: 10.1016/j.coph.2020.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/06/2020] [Indexed: 12/16/2022]
Abstract
Adoptive cellular therapy involves the ex vivo expansion of immune cells, conventionally T cells, before reinfusion back to the patient. Variations in adoptive cellular therapy include transduction of a patient's T cells with either a transgenic T cell receptor or chimeric antigen receptor (CAR) to recognize a defined tumor antigen. Given that adenosine is a major axis of immunosuppression of T cells, particularly in hypoxic tumor microenvironments, therapeutics targeting this pathway are currently being assessed for their potential to enhance adoptive T cell therapies. The use of gene-editing technology, commonly used in tandem with CAR and transgenic T cell receptor (TCR) based adoptive cellular therapy, offers further opportunities to specifically modulate responses to adenosine. This review will discuss recent advances in targeting the adenosine pathway for enhancing the effectiveness of adoptive cellular therapy in the treatment of solid cancers.
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Affiliation(s)
- Kevin Sek
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Lev M Kats
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Phillip K Darcy
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Australia; Department of Immunology, Monash University, Clayton, Australia.
| | - Paul A Beavis
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia.
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Helms RS, Powell JD. Rethinking the adenosine-A 2AR checkpoint: implications for enhancing anti-tumor immunotherapy. Curr Opin Pharmacol 2020; 53:77-83. [PMID: 32781414 DOI: 10.1016/j.coph.2020.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 07/06/2020] [Indexed: 12/16/2022]
Abstract
Adenosine signaling through A2AR serves as a negative regulator of the immune system. Unique to this suppressive pathway is its ability to impact numerous stromal and immune cells. Additionally, tumors exhibit elevated concentrations of adenosine further advancing the pathway's potential as a powerful target for activating anti-tumor immunity. The promise of this therapeutic strategy has been repeatedly demonstrated in mice, but has so far only yielded limited success in the clinic. Nonetheless, it is notable that many of these observed clinical responses have been in individuals resistant to prior immunotherapy. These observations suggest this pathway is indeed involved in tumor immune evasion. Thus, identifying the disparities between the translational and clinical implementation of this therapy becomes necessary. To this end, this review will revisit how and where adenosine-A2AR signaling regulates the immune system and anti-tumor immunity so as to reveal opportunities for improving the translational success of this immunotherapy.
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Affiliation(s)
- Rachel S Helms
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, 1650 Orleans Street, CRB-I Rm443, Baltimore, MD, 21231, USA
| | - Jonathan D Powell
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, 1650 Orleans Street, CRB-I Rm443, Baltimore, MD, 21231, USA.
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D'Arrigo P, Tufano M, Rea A, Vigorito V, Novizio N, Russo S, Romano MF, Romano S. Manipulation of the Immune System for Cancer Defeat: A Focus on the T Cell Inhibitory Checkpoint Molecules. Curr Med Chem 2020; 27:2402-2448. [PMID: 30398102 DOI: 10.2174/0929867325666181106114421] [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] [Received: 04/04/2018] [Revised: 10/15/2018] [Accepted: 10/24/2018] [Indexed: 12/19/2022]
Abstract
The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune-inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1), the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance.
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Affiliation(s)
- Paolo D'Arrigo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Martina Tufano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Anna Rea
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Vincenza Vigorito
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Nunzia Novizio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Salvatore Russo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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50
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Yu F, Zhu C, Xie Q, Wang Y. Adenosine A 2A Receptor Antagonists for Cancer Immunotherapy. J Med Chem 2020; 63:12196-12212. [PMID: 32667814 DOI: 10.1021/acs.jmedchem.0c00237] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Currently, the most promising therapeutic modality for cancer treatment is the blockade of immune checkpoint pathways, which has revolutionized cancer therapy in the past 15 years. Strategies targeting and modulating adenosine A2A receptor (A2AR), an emerging alternative immune checkpoint, have shown the potential to produce significant therapeutic effects. In this review, we describe the immunosuppressive activities of A2AR and A2BR in the tumor microenvironment (TME), followed by a summary and discussion of the structure-activity relationship (SAR) of the A2AR (and dual A2AR/A2BR) antagonists that have been experimentally confirmed to exert oncoimmunological effects. This review also provides an update on the compounds under clinical evaluation and insights into the ligand binding modes of the receptor.
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Affiliation(s)
- Fazhi Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Chenyu Zhu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Yonghui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
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