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Sun Q, Wang Y, Ren H, Hou S, Niu K, Wang L, Liu S, Ye J, Cui C, Qi X. Engineered Hollow Nanocomplex Combining Photothermal and Antioxidant Strategies for Targeted Tregs Depletion and Potent Immune Activation in Tumor Immunotherapy. Adv Healthc Mater 2025; 14:e2405124. [PMID: 40109122 DOI: 10.1002/adhm.202405124] [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: 12/18/2024] [Revised: 03/06/2025] [Indexed: 03/22/2025]
Abstract
In the tumor immunosuppressive microenvironment (TIME), regulatory T cells (Tregs) critically suppress anticancer immunity, characterized by high expression of glucocorticoid-induced TNF receptor (GITR) expression and sensitivity to reactive oxygen species (ROS). This study develops a near-infrared (NIR)-responsive hollow nanocomplex (HPDA-OPC/DTA-1) using hollow polydopamine nanoparticles (HPDA), endowed with thermogenic and antioxidative properties, specifically targeting Tregs to activate antitumor immunity. The GITR agonist DTA-1, combined with the antioxidant oligomeric proanthocyanidins (OPC) to deplete Tregs. However, Tregs depletion alone may not sufficiently trigger robust immune responses. The HPDA nanocarrier enhances thermogenic and antioxidative capacities, supporting photothermal immunotherapy. The HPDA-OPC/DTA-1 demonstrates NIR responsiveness for both photothermal therapy (PTT) and OPC release, while facilitating Tregs depletion via DTA-1 and reducing ROS levels, thereby reviving antitumor immunity. Notably, intratumoral CD4+CD25+FOXP3+ Tregs exhibited a 4.08-fold reduction alongside a 49.11-fold increase in CD8+ T cells/Tregs relative to controls. Enhanced dendritic cells (DCs) maturation and immunogenic cell death (ICD) induction further demonstrate that HPDA-OPC/DTA-1 alleviates immunosuppression and activates antitumor immunity. Ultimately, the observed tumor inhibitory effect (tumor volume: 6.75-fold versus the control) and an over 80% survival rate highlight the therapeutic potential of combining Tregs targeting, antioxidant strategy, and photothermal immunotherapy for effective cancer treatment.
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Affiliation(s)
- Qi Sun
- School of Pharmaceutical Sciences, Laboratory for Clinical Medicine, Capital Medical University, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing, 100069, China
| | - Yuyan Wang
- School of Basic Medicine, Capital Medical University, Beijing, 100069, China
| | - Hetian Ren
- School of Basic Medicine, Capital Medical University, Beijing, 100069, China
| | - Shiyuan Hou
- School of Basic Medicine, Capital Medical University, Beijing, 100069, China
| | - Kaiyi Niu
- School of Basic Medicine, Capital Medical University, Beijing, 100069, China
| | - Liu Wang
- School of Basic Medicine, Capital Medical University, Beijing, 100069, China
| | - Siyu Liu
- School of Pharmaceutical Sciences, Laboratory for Clinical Medicine, Capital Medical University, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing, 100069, China
| | - Jingyi Ye
- School of Pharmaceutical Sciences, Laboratory for Clinical Medicine, Capital Medical University, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing, 100069, China
| | - Chunying Cui
- School of Pharmaceutical Sciences, Laboratory for Clinical Medicine, Capital Medical University, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing, 100069, China
| | - Xianrong Qi
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
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Torres-Mejia E, Weng S, Whittaker CA, Nguyen KB, Duong E, Yim L, Spranger S. Lung Cancer-Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-Dependent CD8+ T-cell Exclusion. Cancer Immunol Res 2025; 13:496-516. [PMID: 39745382 PMCID: PMC11964848 DOI: 10.1158/2326-6066.cir-24-0184] [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: 02/21/2024] [Revised: 10/14/2024] [Accepted: 12/23/2024] [Indexed: 04/03/2025]
Abstract
Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration, creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. In this study, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs.
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Affiliation(s)
- Elen Torres-Mejia
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Sally Weng
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Wellesley College, Wellesley, MA 02481, USA
| | | | - Kim B. Nguyen
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Biology, MIT, Cambridge, MA 02139, USA
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ellen Duong
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Biology, MIT, Cambridge, MA 02139, USA
- Genentech, South San Francisco, CA 94080, USA
| | - Leon Yim
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Stefani Spranger
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Biology, MIT, Cambridge, MA 02139, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
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Ababneh O, Nishizaki D, Kato S, Kurzrock R. Tumor necrosis factor superfamily signaling: life and death in cancer. Cancer Metastasis Rev 2024; 43:1137-1163. [PMID: 39363128 PMCID: PMC11554763 DOI: 10.1007/s10555-024-10206-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/13/2024] [Indexed: 10/05/2024]
Abstract
Immune checkpoint inhibitors have shaped the landscape of cancer treatment. However, many patients either do not respond or suffer from later progression. Numerous proteins can control immune system activity, including multiple tumor necrosis factor (TNF) superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) members; these proteins play a complex role in regulating cell survival and death, cellular differentiation, and immune system activity. Notably, TNFSF/TNFRSF molecules may display either pro-tumoral or anti-tumoral activity, or even both, depending on tumor type. Therefore, TNF is a prototype of an enigmatic two-faced mediator in oncogenesis. To date, multiple anti-TNF agents have been approved and/or included in guidelines for treating autoimmune disorders and immune-related toxicities after immune checkpoint blockade for cancer. A confirmed role for the TNFSF/TNFRSF members in treating cancer has proven more elusive. In this review, we highlight the cancer-relevant TNFSF/TNFRSF family members, focusing on the death domain-containing and co-stimulation members and their signaling pathways, as well as their complicated role in the life and death of cancer cells.
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Affiliation(s)
- Obada Ababneh
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, 22110, Jordan.
| | - Daisuke Nishizaki
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Shumei Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- WIN Consortium, Paris, France.
- Department of Medicine, MCW Cancer Center, Milwaukee, WI, USA.
- Department of Oncology, University of Nebraska, Omaha, NE, USA.
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Serrano A, Zalba S, Lasarte JJ, Troconiz IF, Riva N, Garrido MJ. Quantitative Approach to Explore Regulatory T Cell Activity in Immuno-Oncology. Pharmaceutics 2024; 16:1461. [PMID: 39598584 PMCID: PMC11597491 DOI: 10.3390/pharmaceutics16111461] [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: 10/01/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
The failure of immunotherapies in cancer patients is being widely studied due to the complexities present in the tumor microenvironment (TME), where regulatory T cells (Treg) appear to actively participate in providing an immune escape mechanism for tumors. Therefore, therapies to specifically inhibit tumor-infiltrating Treg represent a challenge, because Treg are distributed throughout the body and provide physiological immune homeostasis to prevent autoimmune diseases. Characterization of immunological and functional profiles could help to identify the mechanisms that need to be inhibited or activated to ensure Treg modulation in the tumor. To address this, quantitative in silico approaches based on mechanistic mathematical models integrating multi-scale information from immune and tumor cells and the effect of different therapies have allowed the building of computational frameworks to simulate different hypotheses, some of which have subsequently been experimentally validated. Therefore, this review presents a list of diverse computational mathematical models that examine the role of Treg as a crucial immune resistance mechanism contributing to the failure of immunotherapy. In addition, this review highlights the relevance of certain molecules expressed in Treg that are associated with the TME immunosuppression, which could be incorporated into the mathematical model for a better understanding of the contribution of Treg modulation. Finally, different preclinical and clinical combinations of molecules are also included to show the trend of new therapies targeting Treg.
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Affiliation(s)
- Alejandro Serrano
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain; (A.S.); (S.Z.); (I.F.T.)
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
| | - Sara Zalba
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain; (A.S.); (S.Z.); (I.F.T.)
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
| | - Juan Jose Lasarte
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
| | - Iñaki F. Troconiz
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain; (A.S.); (S.Z.); (I.F.T.)
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
- Institute of Data Sciences and Artificial Intelligence (DATAI), University of Navarra, 31008 Pamplona, Spain
| | - Natalia Riva
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain; (A.S.); (S.Z.); (I.F.T.)
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
| | - Maria J. Garrido
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain; (A.S.); (S.Z.); (I.F.T.)
- Navarra Institute for Health Research (IdisNA), 31008 Pamplona, Spain
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5
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Dong L, Choi H, Budhu S, Schulze I, Verma S, Mangarin LM, Estrada Nevarro V, Mehanna N, Khan JF, Venkatesh D, Thach D, Rosen N, Wolchok JD, Merghoub T. Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models. Cancer Immunol Res 2024; 12:1392-1408. [PMID: 38885362 DOI: 10.1158/2326-6066.cir-23-0729] [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: 09/12/2023] [Revised: 03/14/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.
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Affiliation(s)
- Lauren Dong
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Hyejin Choi
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Sadna Budhu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Isabell Schulze
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Svena Verma
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Levi M Mangarin
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Valeria Estrada Nevarro
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Nezar Mehanna
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Jonathan F Khan
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Divya Venkatesh
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Daniel Thach
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Neal Rosen
- Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jedd D Wolchok
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Taha Merghoub
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
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6
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Nader NE, Frederico SC, Miller T, Huq S, Zhang X, Kohanbash G, Hadjipanayis CG. Barriers to T Cell Functionality in the Glioblastoma Microenvironment. Cancers (Basel) 2024; 16:3273. [PMID: 39409893 PMCID: PMC11476085 DOI: 10.3390/cancers16193273] [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: 08/21/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 10/20/2024] Open
Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy.
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Affiliation(s)
- Noor E. Nader
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
| | - Stephen C. Frederico
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
- Harvard Medical School, Boston, MA 02115, USA
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Tracy Miller
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
| | - Sakibul Huq
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Xiaoran Zhang
- Sloan Kettering Memorial Cancer Center, New York, NY 10065, USA;
| | - Gary Kohanbash
- Sloan Kettering Memorial Cancer Center, New York, NY 10065, USA;
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7
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Zhang H, Felthaus O, Eigenberger A, Klein S, Prantl L. Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects. Cells 2024; 13:1526. [PMID: 39329710 PMCID: PMC11429654 DOI: 10.3390/cells13181526] [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: 07/30/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
Regulatory T cells (Tregs) play a key role in maintaining immune homeostasis and preventing autoimmunity through their immunosuppressive function. There have been numerous reports confirming that high levels of Tregs in the tumor microenvironment (TME) are associated with a poor prognosis, highlighting their role in promoting an immunosuppressive environment. In breast cancer (BC), Tregs interact with cancer cells, ultimately leading to the suppression of immune surveillance and promoting tumor progression. This review discusses the dual role of Tregs in breast cancer, and explores the controversies and therapeutic potential associated with targeting these cells. Researchers are investigating various strategies to deplete or inhibit Tregs, such as immune checkpoint inhibitors, cytokine antagonists, and metabolic inhibition. However, the heterogeneity of Tregs and the variable precision of treatments pose significant challenges. Understanding the functional diversity of Tregs and the latest advances in targeted therapies is critical for the development of effective therapies. This review highlights the latest approaches to Tregs for BC treatment that both attenuate Treg-mediated immunosuppression in tumors and maintain immune tolerance, and advocates precise combination therapy strategies to optimize breast cancer outcomes.
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Affiliation(s)
- Hanwen Zhang
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany (L.P.)
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Wang H, Divaris K, Pan B, Li X, Lim JH, Saha G, Barovic M, Giannakou D, Korostoff JM, Bing Y, Sen S, Moss K, Wu D, Beck JD, Ballantyne CM, Natarajan P, North KE, Netea MG, Chavakis T, Hajishengallis G. Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss. Cell 2024; 187:3690-3711.e19. [PMID: 38838669 PMCID: PMC11246233 DOI: 10.1016/j.cell.2024.05.003] [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: 08/23/2023] [Revised: 02/19/2024] [Accepted: 05/01/2024] [Indexed: 06/07/2024]
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
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Affiliation(s)
- Hui Wang
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kimon Divaris
- Division of Pediatric and Public Health, Adams School of Dentistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bohu Pan
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA
| | - Xiaofei Li
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Shanghai Jiao Tong University, School of Life Sciences and Biotechnology, Sheng Yushou Center of Cell Biology and Immunology, Shanghai 200240, China
| | - Jong-Hyung Lim
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gundappa Saha
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marko Barovic
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, 01307 Dresden, Germany
| | - Danai Giannakou
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, 01307 Dresden, Germany
| | - Jonathan M Korostoff
- Department of Periodontics, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yu Bing
- Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Souvik Sen
- Department of Neurology, University of South Carolina, Columbia, SC 29209, USA; Center for the Study of Aphasia Recovery, University of South Carolina, Columbia, SC 29209, USA
| | - Kevin Moss
- Department of Biostatistics and Health Data Sciences, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | - Di Wu
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | - James D Beck
- Division of Comprehensive Oral Health-Periodontology, Adams School of Dentistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Pradeep Natarajan
- Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Kari E North
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 XZ Nijmegen, the Netherlands; Department of Immunology and Metabolism, LIMES, University of Bonn, 53115 Bonn, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, 01307 Dresden, Germany
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Song JY, Han MG, Kim Y, Kim MJ, Kang MH, Jeon SH, Kim IA. Combination of local radiotherapy and anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) therapy augments PD-L1 blockade-mediated anti-tumor effects in murine breast cancer model. Radiother Oncol 2024; 190:109981. [PMID: 37925106 DOI: 10.1016/j.radonc.2023.109981] [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: 05/03/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/06/2023]
Abstract
PURPOSE In this study, we investigated whether local radiotherapy (RT) and an anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist could increase the efficacy of PD-L1 blockade. METHODS AND MATERIALS We analyzed a breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to determine the role of GITR in breast cancer. We used the 4T1 murine TNBC model (primary and secondary tumors) to investigate the efficacy of PD-L1 blockade, local RT, anti-GITR agonist, and their combinations. We assessed tumor growth by tumor volume measurements, in vivo bioluminescence imaging, and metastatic lung nodule counts to evaluate the effects of these treatments. Flow cytometry and immunohistochemistry determined the proportions and phenotypes of CD8+ T-cells and regulatory T-cells (Tregs) in the tumors and spleen. Plasma cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS In the METABRIC cohort, patients with high expression of TNFRSF18, which encodes GITR, had significantly better survival than those with low expression. Adding local RT or anti-GITR agonist to PD-L1 blockade did not significantly augment efficacy compared to PD-L1 blockade alone; however, adding both to PD-L1 blockade significantly reduced tumor growth and lung metastasis. The benefits of the triple combination were accompanied by increased CD8+ T-cells and decreased Tregs in the tumor microenvironment and spleen. CONCLUSIONS The combination of local RT and an anti-GITR agonist significantly enhanced the anti-tumor immune responses induced by PD-L1 blockade. These results provide the preclinical rationale for the combination of therapy.
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Affiliation(s)
- Jun Yeong Song
- Department of Radiation Oncology, Seoul National University School of Medicine, Republic of Korea.
| | - Min Guk Han
- Medical Science Research Institute, Seoul National University Bundang Hospital, Republic of Korea
| | - Yoomin Kim
- Department of Tumor Biology, Graduate School of Medicine & Cancer Research Institute, Seoul National University, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Republic of Korea
| | - Min Ji Kim
- Department of Tumor Biology, Graduate School of Medicine & Cancer Research Institute, Seoul National University, Republic of Korea
| | - Mi Hyun Kang
- Medical Science Research Institute, Seoul National University Bundang Hospital, Republic of Korea
| | - Seung Hyuck Jeon
- Department of Radiation Oncology, Seoul National University Bundang Hospital, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Republic of Korea
| | - In Ah Kim
- Department of Radiation Oncology, Seoul National University School of Medicine, Republic of Korea; Department of Radiation Oncology, Seoul National University Bundang Hospital, Republic of Korea; Department of Tumor Biology, Graduate School of Medicine & Cancer Research Institute, Seoul National University, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Republic of Korea.
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10
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Hosseinalizadeh H, Rabiee F, Eghbalifard N, Rajabi H, Klionsky DJ, Rezaee A. Regulating the regulatory T cells as cell therapies in autoimmunity and cancer. Front Med (Lausanne) 2023; 10:1244298. [PMID: 37828948 PMCID: PMC10565010 DOI: 10.3389/fmed.2023.1244298] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/01/2023] [Indexed: 10/14/2023] Open
Abstract
Regulatory T cells (Tregs), possess a pivotal function in the maintenance of immune homeostasis. The dysregulated activity of Tregs has been associated with the onset of autoimmune diseases and cancer. Hence, Tregs are promising targets for interventions aimed at steering the immune response toward the desired path, either by augmenting the immune system to eliminate infected and cancerous cells or by dampening it to curtail the damage to self-tissues in autoimmune disorders. The activation of Tregs has been observed to have a potent immunosuppressive effect against T cells that respond to self-antigens, thus safeguarding our body against autoimmunity. Therefore, promoting Treg cell stability presents a promising strategy for preventing or managing chronic inflammation that results from various autoimmune diseases. On the other hand, Tregs have been found to be overactivated in several forms of cancer, and their role as immune response regulators with immunosuppressive properties poses a significant impediment to the successful implementation of cancer immunotherapy. However, the targeting of Tregs in a systemic manner may lead to the onset of severe inflammation and autoimmune toxicity. It is imperative to develop more selective methods for targeting the function of Tregs in tumors. In this review, our objective is to elucidate the function of Tregs in tumors and autoimmunity while also delving into numerous therapeutic strategies for reprogramming their function. Our focus is on reprogramming Tregs in a highly activated phenotype driven by the activation of key surface receptors and metabolic reprogramming. Furthermore, we examine Treg-based therapies in autoimmunity, with a specific emphasis on Chimeric Antigen Receptor (CAR)-Treg therapy and T-cell receptor (TCR)-Treg therapy. Finally, we discuss key challenges and the future steps in reprogramming Tregs that could lead to the development of novel and effective cancer immunotherapies.
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Affiliation(s)
- Hamed Hosseinalizadeh
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Fatemeh Rabiee
- Department of Pharmacology and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Negar Eghbalifard
- Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Rajabi
- Faculty of Medicine, ShahreKord University of Medical Sciences, Shahrekord, Iran
| | - Daniel J. Klionsky
- Department of Molecular, Cellular and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
| | - Aryan Rezaee
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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11
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Advances in antibody-based therapy in oncology. NATURE CANCER 2023; 4:165-180. [PMID: 36806801 DOI: 10.1038/s43018-023-00516-z] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 01/10/2023] [Indexed: 02/22/2023]
Abstract
Monoclonal antibodies are a growing class of targeted cancer therapeutics, characterized by exquisite specificity, long serum half-life, high affinity and immune effector functions. In this review, we outline key advances in the field with a particular focus on recent and emerging classes of engineered antibody therapeutic candidates, discuss molecular structure and mechanisms of action and provide updates on clinical development and practice.
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12
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Li Q, Lu J, Li J, Zhang B, Wu Y, Ying T. Antibody-based cancer immunotherapy by targeting regulatory T cells. Front Oncol 2023; 13:1157345. [PMID: 37182149 PMCID: PMC10174253 DOI: 10.3389/fonc.2023.1157345] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
Regulatory T cells (Tregs) are among the most abundant suppressive cells, which infiltrate and accumulate in the tumor microenvironment, leading to tumor escape by inducing anergy and immunosuppression. Their presence has been correlated with tumor progression, invasiveness and metastasis. Targeting tumor-associated Tregs is an effective addition to current immunotherapy approaches, but it may also trigger autoimmune diseases. The major limitation of current therapies targeting Tregs in the tumor microenvironment is the lack of selective targets. Tumor-infiltrating Tregs express high levels of cell surface molecules associated with T-cell activation, such as CTLA4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor superfamily members including 4-1BB, OX40, and GITR. Targeting these molecules often attribute to concurrent depletion of antitumor effector T-cell populations. Therefore, novel approaches need to improve the specificity of targeting Tregs in the tumor microenvironment without affecting peripheral Tregs and effector T cells. In this review, we discuss the immunosuppressive mechanisms of tumor-infiltrating Tregs and the status of antibody-based immunotherapies targeting Tregs.
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Affiliation(s)
- Quanxiao Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jun Lu
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Baohong Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yanling Wu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Tianlei Ying, ; Yanling Wu,
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Tianlei Ying, ; Yanling Wu,
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13
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McRitchie BR, Akkaya B. Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment. Front Immunol 2022; 13:940052. [PMID: 36248808 PMCID: PMC9562032 DOI: 10.3389/fimmu.2022.940052] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals' genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+ T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+ T cells and CD8+ T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+ T cells and CD8+ T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
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Affiliation(s)
- Bayley R. McRitchie
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Billur Akkaya
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The College of Medicine, The Ohio State University, Columbus, OH, United States
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14
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Reitinger C, Ipsen-Escobedo A, Hornung C, Heger L, Dudziak D, Lux A, Nimmerjahn F. Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity. Front Immunol 2022; 13:970290. [PMID: 36248847 PMCID: PMC9558126 DOI: 10.3389/fimmu.2022.970290] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.
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Affiliation(s)
- Carmen Reitinger
- Chair of Genetics, Department of Biology, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Andrea Ipsen-Escobedo
- Chair of Genetics, Department of Biology, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Chiara Hornung
- Chair of Genetics, Department of Biology, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Lukas Heger
- Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Diana Dudziak
- Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
- Medical Immunology Campus Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Anja Lux
- Chair of Genetics, Department of Biology, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Falk Nimmerjahn
- Chair of Genetics, Department of Biology, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, Erlangen, Germany
- *Correspondence: Falk Nimmerjahn,
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15
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Santiago-Sánchez GS, Hodge JW, Fabian KP. Tipping the scales: Immunotherapeutic strategies that disrupt immunosuppression and promote immune activation. Front Immunol 2022; 13:993624. [PMID: 36159809 PMCID: PMC9492957 DOI: 10.3389/fimmu.2022.993624] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy has emerged as an effective therapeutic approach for several cancer types. However, only a subset of patients exhibits a durable response due in part to immunosuppressive mechanisms that allow tumor cells to evade destruction by immune cells. One of the hallmarks of immune suppression is the paucity of tumor-infiltrating lymphocytes (TILs), characterized by low numbers of effector CD4+ and CD8+ T cells in the tumor microenvironment (TME). Additionally, the proper activation and function of lymphocytes that successfully infiltrate the tumor are hampered by the lack of co-stimulatory molecules and the increase in inhibitory factors. These contribute to the imbalance of effector functions by natural killer (NK) and T cells and the immunosuppressive functions by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the TME, resulting in a dysfunctional anti-tumor immune response. Therefore, therapeutic regimens that elicit immune responses and reverse immune dysfunction are required to counter immune suppression in the TME and allow for the re-establishment of proper immune surveillance. Immuno-oncology (IO) agents, such as immune checkpoint blockade and TGF-β trapping molecules, have been developed to decrease or block suppressive factors to enable the activity of effector cells in the TME. Therapeutic agents that target immunosuppressive cells, either by direct lysis or altering their functions, have also been demonstrated to decrease the barrier to effective immune response. Other therapies, such as tumor antigen-specific vaccines and immunocytokines, have been shown to activate and improve the recruitment of CD4+ and CD8+ T cells to the tumor, resulting in improved T effector to Treg ratio. The preclinical data on these diverse IO agents have led to the development of ongoing phase I and II clinical trials. This review aims to provide an overview of select therapeutic strategies that tip the balance from immunosuppression to immune activity in the TME.
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16
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Wiles KN, Tsikretsis LE, Alioto C, de Viveiros PH, Villaflor VM, Tétreault MP. GITR agonistic stimulation enhances the anti-tumor immune response in a mouse model of ESCC. Carcinogenesis 2022; 43:908-918. [PMID: 35880612 PMCID: PMC9587681 DOI: 10.1093/carcin/bgac064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/12/2022] [Accepted: 07/21/2022] [Indexed: 11/12/2022] Open
Abstract
Esophageal cancer is a significant health burden in the United States and worldwide and is the 8 th leading cause of cancer-related death. Over 90% of esophageal cancers are squamous cell cancers (ESCC). Despite the development of new therapies, the overall 5-year survival rate remains lower than 20%. Recent clinical trials of immunotherapy approaches in ESCC have shown that blocking PD-1/PD-L1 interactions can reduce tumor burden and increase survival, but this only occurs in a fraction of patients. This emphasizes the need for additional therapeutic options to improve overall response rates, duration of response, and overall survival. Glucocorticoid-induced TNFR-related protein (GITR) stimulation has emerged as a promising immunotherapy target, as its stimulation appears to promote tumor regression. In this study, we evaluated the consequences of GITR agonistic stimulation with the DTA-1 antibody (anti-GITR agonist) on esophageal squamous cell carcinoma (ESCC) progression. Increased expression of GITR was observed in esophageal tumors from ESCC patients in comparison to normal adjacent tissue and in a mouse model of ESCC. 100% of mice treated with 4-NQO/IgG control antibody developed invasive squamous cell carcinoma. Less advanced esophageal tumors were seen in mice treated with 4-NQO/anti-GITR agonist compared to 4-NQO/IgG treatment. 4-NQO/anti-GITR agonist-treated mice demonstrated a significant increase in mucosal CTL/Treg ratios as well as decreased gene expression profiles of pathways related to esophageal squamous cell carcinogenesis. Thus, GITR agonism merits further study as a treatment strategy for ESCC patients.
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Affiliation(s)
- Kelsey Nicole Wiles
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611-3010, USA
| | - Lia Elyse Tsikretsis
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611-3010, USA
| | - Cara Alioto
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611-3010, USA
| | - Pedro Hermida de Viveiros
- Department of Medicine, Hematology and Oncology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611-3010, USA
| | - Victoria M Villaflor
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611-3010, USA
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17
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Wight AE, Sido JM, Degryse S, Ao L, Nakagawa H, Qiu(Vivian) Y, Shen X, Oseghali O, Kim HJ, Cantor H. Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy. Proc Natl Acad Sci U S A 2022; 119:e2200757119. [PMID: 35482921 PMCID: PMC9170135 DOI: 10.1073/pnas.2200757119] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/31/2022] [Indexed: 11/18/2022] Open
Abstract
Regulatory T cells (Treg) can impede antitumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represents an optimal approach to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL12 cytokine, the production of γ-interferon, and the recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to glucocorticoid-induced TNFR-related protein (GITR) activation, we examined the impact of the coordinate induction of the two destabilization pathways on antitumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic antitumor responses. These findings indicate that the delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers.
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Affiliation(s)
- Andrew E. Wight
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Jessica M. Sido
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Sandrine Degryse
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Lin Ao
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Hidetoshi Nakagawa
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Yiguo Qiu(Vivian)
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Xianli Shen
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Oba Oseghali
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
| | - Hye-Jung Kim
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | - Harvey Cantor
- Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, MA 02115
- Department of Immunology, Harvard Medical School, Boston, MA 02115
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18
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Lee J, Kim D, Min B. Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease. Front Immunol 2022; 13:865593. [PMID: 35359918 PMCID: PMC8963273 DOI: 10.3389/fimmu.2022.865593] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/22/2022] [Indexed: 01/04/2023] Open
Abstract
Foxp3+ regulatory T (Treg) cells are a CD4 T cell subset with unique immune regulatory function that are indispensable in immunity and tolerance. Their indisputable importance has been investigated in numerous disease settings and experimental models. Despite the extensive efforts in determining the cellular and molecular mechanisms operating their functions, our understanding their biology especially in vivo remains limited. There is emerging evidence that Treg cells resident in the non-lymphoid tissues play a central role in regulating tissue homeostasis, inflammation, and repair. Furthermore, tissue-specific properties of those Treg cells that allow them to express tissue specific functions have been explored. In this review, we will discuss the potential mechanisms and key cellular/molecular factors responsible for the homeostasis and functions of tissue resident Treg cells under steady-state and inflammatory conditions.
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Affiliation(s)
- Juyeun Lee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Dongkyun Kim
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Booki Min
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- *Correspondence: Booki Min,
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19
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Kleinman AJ, Pandrea I, Apetrei C. So Pathogenic or So What?-A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research. Viruses 2022; 14:135. [PMID: 35062339 PMCID: PMC8781889 DOI: 10.3390/v14010135] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/10/2021] [Accepted: 12/25/2021] [Indexed: 02/07/2023] Open
Abstract
HIV infection requires lifelong antiretroviral therapy (ART) to control disease progression. Although ART has greatly extended the life expectancy of persons living with HIV (PWH), PWH nonetheless suffer from an increase in AIDS-related and non-AIDS related comorbidities resulting from HIV pathogenesis. Thus, an HIV cure is imperative to improve the quality of life of PWH. In this review, we discuss the origins of various SIV strains utilized in cure and comorbidity research as well as their respective animal species used. We briefly detail the life cycle of HIV and describe the pathogenesis of HIV/SIV and the integral role of chronic immune activation and inflammation on disease progression and comorbidities, with comparisons between pathogenic infections and nonpathogenic infections that occur in natural hosts of SIVs. We further discuss the various HIV cure strategies being explored with an emphasis on immunological therapies and "shock and kill".
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Affiliation(s)
- Adam J. Kleinman
- Division of Infectious Diseases, DOM, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
| | - Ivona Pandrea
- Department of Infectious Diseases and Immunology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA;
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Cristian Apetrei
- Division of Infectious Diseases, DOM, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
- Department of Infectious Diseases and Immunology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA;
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20
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Stirling ER, Bronson SM, Mackert JD, Cook KL, Triozzi PL, Soto-Pantoja DR. Metabolic Implications of Immune Checkpoint Proteins in Cancer. Cells 2022; 11:179. [PMID: 35011741 PMCID: PMC8750774 DOI: 10.3390/cells11010179] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 12/29/2022] Open
Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
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Affiliation(s)
- Elizabeth R. Stirling
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
| | - Steven M. Bronson
- Department of Pathology, Section of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jessica D. Mackert
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Katherine L. Cook
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
| | - Pierre L. Triozzi
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
- Department of Hematology and Oncology, Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
| | - David R. Soto-Pantoja
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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21
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Kos K, de Visser KE. The Multifaceted Role of Regulatory T Cells in Breast Cancer. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2021; 5:291-310. [PMID: 34632244 PMCID: PMC7611782 DOI: 10.1146/annurev-cancerbio-042920-104912] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies.
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Affiliation(s)
- Kevin Kos
- Division of Tumor Biology and Immunology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Karin E de Visser
- Division of Tumor Biology and Immunology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.,Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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22
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Zhao M, Fu L, Chai Y, Sun M, Li Y, Wang S, Qi J, Zeng B, Kang L, Gao GF, Tan S. Atypical TNF-TNFR superfamily binding interface in the GITR-GITRL complex for T cell activation. Cell Rep 2021; 36:109734. [PMID: 34551288 DOI: 10.1016/j.celrep.2021.109734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/16/2021] [Accepted: 08/26/2021] [Indexed: 10/20/2022] Open
Abstract
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a critical regulatory molecule in modulation of T cell immune responses. Here we report the mouse GITR (mGITR) and mGITR ligand (mGITRL) complex structure and find that the binding interface of mGITR and mGITRL is distinct from the typical tumor necrosis factor superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) members. mGITR binds to its ligand with a single domain, whereas the binding interface on mGITRL is located on the side, which is distal from conserved binding sites of TNFSF molecules. Mutational analysis reveals that the binding interface of GITR/GITRL in humans is conserved with that in the mouse. Substitution of key interacting D93-I94-V95 (DIV) in mGITR with the corresponding K93-F94-S95 (KFS) in human GITR enables cross-recognition with human GITRL and cross-activation of receptor signaling. The findings of this study substantially expand our understanding of the interaction of TNFSF/TNFRSF superfamily molecules and can benefit the future design of biologics by targeting GITR/GITRL.
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Affiliation(s)
- Min Zhao
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Lijun Fu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang 330013, China
| | - Yan Chai
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Meng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Yan Li
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Shuo Wang
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jianxun Qi
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Bin Zeng
- College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang 330013, China; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
| | - Le Kang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - George F Gao
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Shuguang Tan
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
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23
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Buzzatti G, Dellepiane C, Del Mastro L. New emerging targets in cancer immunotherapy: the role of GITR. ESMO Open 2021; 4:e000738. [PMID: 32817129 PMCID: PMC7451269 DOI: 10.1136/esmoopen-2020-000738] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/15/2020] [Accepted: 06/19/2020] [Indexed: 12/14/2022] Open
Abstract
In the last decade, immunotherapies have revolutionised anticancer treatment. However, there is still a number of patients that do not respond or acquire resistance to these treatments. Despite several efforts to combine immunotherapy with other strategies like chemotherapy, or other immunotherapy, there is an 'urgent' need to better understand the immune landscape of the tumour microenvironment. New promising approaches, in addition to blocking co-inhibitory pathways, such those cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 mediated, consist of activating co-stimulatory pathways to enhance antitumour immune responses. Among several new targets, glucocorticoid-induced TNFR-related gene (GITR) activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity in vitro and in vivo enhancing CD8+ and CD4+ effector T-cell activity and depleting tumour-infiltrating Tregs. Phase I clinical trials reported a manageable safety profile of GITR mAbs. However, monotherapy seems not to be effective, whereas responses have been reported in combination therapy, in particular adding PD-1 blockade. Several clinical studies are ongoing and results are awaited to further develop GITR-stimulating treatments.
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Affiliation(s)
- Giulia Buzzatti
- U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
| | - Chiara Dellepiane
- U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Lucia Del Mastro
- U.O. Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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24
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Murakami J, Wu L, Kohno M, Chan ML, Zhao Y, Yun Z, Cho BCJ, de Perrot M. Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma. Sci Transl Med 2021; 13:13/589/eabd9882. [PMID: 33853932 DOI: 10.1126/scitranslmed.abd9882] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 03/15/2021] [Indexed: 12/20/2022]
Abstract
Malignant pleural mesothelioma (MPM) is an intractable disease with an extremely poor prognosis. Our clinical protocol for MPM of subablative radiotherapy (RT) followed by radical surgery achieved better survival compared to other multimodal treatments, but local relapse and metastasis remain a problem. This subablative RT elicits an antitumoral immune response that is limited by the immunosuppressive microenvironment generated by regulatory T (Treg) cells. The antitumor effect of immunotherapy to simultaneously modulate the immune activation and the immune suppression after subablative RT has not been investigated in MPM. Herein, we demonstrated a rationale to combine interleukin-15 (IL-15) superagonist (IL-15SA) and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist (DTA-1) with subablative RT in mesothelioma. IL-15SA boosted the systemic expansion of specific antitumoral memory CD8+ T cells that were induced by RT in mice. Their effect, however, was limited by the up-regulation and activation of Treg cells in the radiated tumor microenvironment. Hence, selective depletion of intratumoral Treg cells through DTA-1 enhanced the benefit of subablative RT in combination with IL-15SA. The addition of surgical resection of the radiated tumor in combination with IL-15SA and DTA-1 maximized the benefit of RT and was accompanied by a reproducible abscopal response in a concomitant tumor model. These data support the development of clinical trials in MPM to test such treatment options for patients with locally advanced or metastatic tumors.
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Affiliation(s)
- Junichi Murakami
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.,Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Licun Wu
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Mikihiro Kohno
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.,Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada
| | - Mei-Lin Chan
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Yidan Zhao
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Zhihong Yun
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - B C John Cho
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada
| | - Marc de Perrot
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada. .,Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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25
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Pourakbari R, Hajizadeh F, Parhizkar F, Aghebati-Maleki A, Mansouri S, Aghebati-Maleki L. Co-stimulatory agonists: An insight into the immunotherapy of cancer. EXCLI JOURNAL 2021; 20:1055-1085. [PMID: 34267616 PMCID: PMC8278219 DOI: 10.17179/excli2021-3522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022]
Abstract
Immune checkpoint pathways consist of stimulatory pathways, which can function like a strong impulse to promote T helper cells or killer CD8+ cells activation and proliferation. On the other hand, inhibitory pathways keep self-tolerance of the immune response. Increasing immunological activity by stimulating and blocking these signaling pathways are recognized as immune checkpoint therapies. Providing the best responses of CD8+ T cell needs the activation of T cell receptor along with the co-stimulation that is generated via stimulatory checkpoint pathways ligation including Inducible Co-Stimulator (ICOS), CD40, 4-1BB, GITR, and OX40. In cancer, programmed cell death receptor-1 (PD-1), Programmed cell death ligand-1(PD-L1) and Cytotoxic T Lymphocyte-Associated molecule-4 (CTLA-4) are the most known inhibitory checkpoint pathways, which can hinder the immune responses which have specifically anti-tumor characteristics and attenuate T cell activation and also cytokine production. The use of antagonistic monoclonal antibodies (mAbs) that block CTLA-4 or PD-1 activation is used in a variety of malignancies. It has been reported that they can lead to an increase in T cells and thereby strengthen anti-tumor immunity. Agonists of stimulatory checkpoint pathways can induce strong immunologic responses in metastatic patients; however, for achieving long-lasting benefits for the wide range of patients, efficient combinatorial therapies are required. In the present review, we focus on the preclinical and basic research on the molecular and cellular mechanisms by which immune checkpoint inhibitor blockade or other approaches with co-stimulatory agonists work together to improve T-cell antitumor immunity.
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Affiliation(s)
- Ramin Pourakbari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Hajizadeh
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Parhizkar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebati-Maleki
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanaz Mansouri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, Krishnan S, Posada JM, Ghosh M, Mamessier E, Wong C, Ferraro GB, Batista A, Wang N, Badeaux M, Roberge S, Xu L, Huang P, Shalek AK, Fukumura D, Kim HJ, Jain RK. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun 2021; 12:2582. [PMID: 33976133 PMCID: PMC8113440 DOI: 10.1038/s41467-021-22885-8] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
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Affiliation(s)
- Zohreh Amoozgar
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Jonas Kloepper
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Jun Ren
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Rong En Tay
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA, USA
| | - Samuel W Kazer
- Department of Chemistry, Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Broad Institute of MIT and Harvard University, Cambridge, MA, USA
- Ragon Institute of MGH, MIT & Harvard, Cambridge, MA, USA
- Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Evgeny Kiner
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Shanmugarajan Krishnan
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Jessica M Posada
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Mitrajit Ghosh
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Emilie Mamessier
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Christina Wong
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Gino B Ferraro
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Ana Batista
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Nancy Wang
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Mark Badeaux
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Sylvie Roberge
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Lei Xu
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Peigen Huang
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Alex K Shalek
- Department of Chemistry, Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Broad Institute of MIT and Harvard University, Cambridge, MA, USA
- Ragon Institute of MGH, MIT & Harvard, Cambridge, MA, USA
- Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA
| | - Hye-Jung Kim
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA, USA.
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA.
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27
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Ciobanasu C. Peptides-based therapy and diagnosis. Strategies for non-invasive therapies in cancer. J Drug Target 2021; 29:1063-1079. [PMID: 33775187 DOI: 10.1080/1061186x.2021.1906885] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In recent years, remarkable progress was registered in the field of cancer research. Though, cancer still represents a major cause of death and cancer metastasis a problem seeking for urgent solutions as it is the main reason for therapeutic failure. Unfortunately, the most common chemotherapeutic agents are non-selective and can damage healthy tissues and cause side effects that affect dramatically the quality of life of the patients. Targeted therapy with molecules that act specifically at the tumour sites interacting with overexpressed cancer receptors is a very promising strategy for achieving the specific delivery of anticancer drugs, radioisotopes or imaging agents. This review aims to give an overview on different strategies for targeting cancer cell receptors localised either at the extracellular matrix or at the cell membrane. Molecules like antibodies, aptamers and peptides targeting the cell surface are presented with advantages and disadvantages, with emphasis on peptides. The most representative peptides are described, including cell penetrating peptides, homing and anticancer peptides with particular consideration on recent discoveries.
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Affiliation(s)
- Corina Ciobanasu
- Sciences Department, Institute for Interdisciplinary Research, Alexandru I. Cuza University, Iaşi, Romania
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28
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Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, Yan M, Chang WC, Hsu JM, Cha JH, Hsu JL, Chou CW, Sun X, Deng Y, Chou CK, Yu D, Hung MC. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 2021; 12:832. [PMID: 33547304 PMCID: PMC7864927 DOI: 10.1038/s41467-021-21099-2] [Citation(s) in RCA: 350] [Impact Index Per Article: 87.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 01/07/2021] [Indexed: 01/30/2023] Open
Abstract
The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/immunology
- Adenocarcinoma/mortality
- Adenocarcinoma/therapy
- Animals
- Antibodies/pharmacology
- Antineoplastic Agents, Immunological/pharmacology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/mortality
- Colonic Neoplasms/therapy
- Galectins/antagonists & inhibitors
- Galectins/genetics
- Galectins/immunology
- Gene Expression Regulation, Neoplastic/immunology
- Glucocorticoid-Induced TNFR-Related Protein/agonists
- Glucocorticoid-Induced TNFR-Related Protein/genetics
- Glucocorticoid-Induced TNFR-Related Protein/immunology
- Hepatitis A Virus Cellular Receptor 2/genetics
- Hepatitis A Virus Cellular Receptor 2/immunology
- Humans
- Immunotherapy/methods
- Jurkat Cells
- Melanoma, Experimental/genetics
- Melanoma, Experimental/immunology
- Melanoma, Experimental/mortality
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred BALB C
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- Protein Binding
- Signal Transduction
- Skin Neoplasms/genetics
- Skin Neoplasms/immunology
- Skin Neoplasms/mortality
- Skin Neoplasms/therapy
- Survival Analysis
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/pathology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
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Affiliation(s)
- Riyao Yang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Linlin Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ching-Fei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yu-Han Wang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Jun Yao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Meisi Yan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Wei-Chao Chang
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Jung-Mao Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Jong-Ho Cha
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
| | - Jennifer L Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cheng-Wei Chou
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
- Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Xian Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yalan Deng
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chao-Kai Chou
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
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29
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The role of regulatory T cells in the pathogenesis and treatment of prostate cancer. Life Sci 2021; 284:119132. [PMID: 33513396 DOI: 10.1016/j.lfs.2021.119132] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/10/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Despite developments in the treatment of various cancers, prostate cancer is one of the deadliest diseases known to men. Systemic therapies such as androgen deprivation, chemotherapy, and radiation therapy have not been very successful in treating this disease. Numerous studies have shown that there is a direct relationship between cancer progression and inhibition of anti-tumor immune responses that can lead to progression of various malignancies, including prostate cancer. Interestingly, CD4+CD25+FoxP3+ regulatory T cells significantly accumulate and increase in draining lymph nodes and PBMCs of patients with prostate cancer and other solid tumors. In vivo and in vitro studies have shown that Tregs can suppress anti-tumor responses, which is directly related to the increased risk of cancer recurrence. Tregs are essential for preserving self-tolerance and inhibiting extra immune responses harmful to the host. Since the tumor-related antigens are mainly self-antigens, Tregs could play a major role in tumor progression. Accordingly, it has discovered that prostate cancer patients with higher Tregs have poor prognosis and low survival rates. However, anti-tumor responses can be reinforced by suppression of Tregs with using monoclonal antibodies against CD25 and CTLA-4. Therefore, depleting Tregs or suppressing their functions could be one of the effective ways for prostate cancer immunotherapy. The purpose of this review is to investigate the role of Treg cells in the progression of prostate cancer and to evaluate effective strategies for the treatment of prostate cancer by regulating Treg cells.
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30
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Dadey RE, Workman CJ, Vignali DAA. Regulatory T Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1273:105-134. [PMID: 33119878 DOI: 10.1007/978-3-030-49270-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Regulatory T cells (Tregs) are an immunosuppressive subpopulation of CD4+ T cells that are endowed with potent suppressive activity and function to limit immune activation and maintain homeostasis. These cells are identified by the hallmark transcription factor FOXP3 and the high-affinity interleukin-2 (IL-2) receptor chain CD25. Tregs can be recruited to and persist within the tumor microenvironment (TME), acting as a potent barrier to effective antitumor immunity. This chapter will discuss [i] the history and hallmarks of Tregs; [ii] the recruitment, development, and persistence of Tregs within the TME; [iii] Treg function within TME; asnd [iv] the therapeutic targeting of Tregs in the clinic. This chapter will conclude with a discussion of likely trends and future directions.
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Affiliation(s)
- Rebekah E Dadey
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Creg J Workman
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. .,Tumor Microenvironment Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA. .,Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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31
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Gaissmaier L, Christopoulos P. Immune Modulation in Lung Cancer: Current Concepts and Future Strategies. Respiration 2020; 99:1-27. [PMID: 33291116 DOI: 10.1159/000510385] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/10/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15-25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.
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Affiliation(s)
- Lena Gaissmaier
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany,
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany,
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32
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Yang F, Zhao L, Wei Z, Yang Y, Liu J, Li Y, Tian X, Liu X, Lü X, Sui J. A Cross-Species Reactive TIGIT-Blocking Antibody Fc Dependently Confers Potent Antitumor Effects. THE JOURNAL OF IMMUNOLOGY 2020; 205:2156-2168. [PMID: 32887749 DOI: 10.4049/jimmunol.1901413] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 08/08/2020] [Indexed: 12/13/2022]
Abstract
The T cell immunoreceptor with Ig and ITIM domains (TIGIT) has been shown to exert inhibitory roles in antitumor immune responses. In this study, we report the development of a human mAb, T4, which recognizes both human and mouse TIGIT and blocks the interaction of TIGIT with its ligand CD155 in both species. The T4 Ab targets the segment connecting F and G strands of TIGIT's extracellular IgV domain, and we show in studies with mouse tumor models that the T4 Ab exerts strong antitumor activity and induces durable immune memory against various tumor types. Mechanistically, we demonstrate that the T4 Ab's antitumor effects are mediated via multiple immunological impacts, including a CD8+ T immune response and Fc-mediated effector functions, through NK cells that cause significant reduction in the frequency of intratumoral T regulatory cells (Tregs). Notably, this Treg reduction apparently activates additional antitumor CD8+ T cell responses, targeting tumor-shared Ags that are normally cryptic or suppressed by Tregs, thus conferring cross-tumor immune memory. Subsequent engineering for Fc variants of the T4 Ab with enhanced Fc-mediated effector functions yielded yet further improvements in antitumor efficacy. Thus, beyond demonstrating the T4 Ab as a promising candidate for the development of cancer immunotherapies, our study illustrates how the therapeutic efficacy of an anti-TIGIT Ab can be improved by enhancing Fc-mediated immune effector functions. Our insights about the multiple mechanisms of action of the T4 Ab and its Fc variants should help in developing new strategies that can realize the full clinical potential of anti-TIGIT Ab therapies.
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Affiliation(s)
- Fang Yang
- College of Biological Sciences, China Agricultural University, Beijing 100193, China.,National Institute of Biological Sciences, Beijing 102206, China
| | - Linlin Zhao
- National Institute of Biological Sciences, Beijing 102206, China.,Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhizhong Wei
- National Institute of Biological Sciences, Beijing 102206, China.,Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yajing Yang
- National Institute of Biological Sciences, Beijing 102206, China.,Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Juan Liu
- National Institute of Biological Sciences, Beijing 102206, China
| | - Yulu Li
- National Institute of Biological Sciences, Beijing 102206, China.,Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, College of Life Sciences, Peking University, Beijing 100871, China; and
| | - Xinxin Tian
- National Institute of Biological Sciences, Beijing 102206, China
| | - Ximing Liu
- National Institute of Biological Sciences, Beijing 102206, China
| | - Xueyuan Lü
- National Institute of Biological Sciences, Beijing 102206, China.,Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jianhua Sui
- National Institute of Biological Sciences, Beijing 102206, China; .,Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
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33
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Balmanoukian AS, Infante JR, Aljumaily R, Naing A, Chintakuntlawar AV, Rizvi NA, Ross HJ, Gordon M, Mallinder PR, Elgeioushi N, González-García I, Standifer N, Cann J, Durham N, Rahimian S, Kumar R, Denlinger CS. Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors. Clin Cancer Res 2020; 26:6196-6203. [PMID: 32887725 DOI: 10.1158/1078-0432.ccr-20-0452] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 07/07/2020] [Accepted: 09/01/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. PATIENTS AND METHODS Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. RESULTS Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. CONCLUSIONS MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
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Affiliation(s)
| | | | | | - Aung Naing
- MD Anderson Cancer Center, Houston, Texas
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34
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Zhu MMT, Burugu S, Gao D, Yu J, Kos Z, Leung S, Horst BA, Nielsen TO. Evaluation of glucocorticoid-induced TNF receptor (GITR) expression in breast cancer and across multiple tumor types. Mod Pathol 2020; 33:1753-1763. [PMID: 32350416 DOI: 10.1038/s41379-020-0550-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 04/04/2020] [Accepted: 04/05/2020] [Indexed: 12/18/2022]
Abstract
Glucocorticoid-induced TNF receptor (GITR) is an emerging immunotherapy target that is expressed at high levels on regulatory T cells. Agonistic anti-GITR antibodies have anti-tumor activity in cancer mouse models, and recent phase 1 trials have demonstrated their safe pharmacological profile. However, there is limited knowledge on the relationship between GITR expression and the tumor microenvironment. GITR protein expression was assayed by immunohistochemistry on 3992 breast cancer surgical excision specimens assembled into tissue microarrays and scored visually by a pathologist for GITR expression on tumor-infiltrating lymphocytes and on carcinoma cells. GITR expression by the malignant cells was further surveyed in gastrointestinal stromal tumor (N = 713), lung carcinoma (N = 705), pancreatic cancer (N = 486), ovarian cancer (N = 445), bladder cancer (N = 88), prostate cancer (N = 88), testicular cancer (N = 76), melanoma (N = 75), renal cell carcinoma (N = 68), epithelioid sarcoma (N = 53), and neuroendocrine tumors (N = 41). In breast cancer, GITR expression on tumor-infiltrating lymphocytes (12.4%) correlated with other immune response biomarkers (PD-L1+ on tumor cells, and PD-1+, LAG-3+, TIM-3+ lymphocytes; p < 0.001), and T-cell markers (CD8+, FOXP3+; p < 0.001). GITR+ carcinoma cells were observed in 6.0% of breast cancer cases and correlated with worse relapse-free survival (p = 0.015). Among the additional tumor types examined, cancers with GITR+ malignant cells included bladder cancer (5.7%), primary (but not metastatic) melanoma (4.5%), and ovarian cancer (3.2%); no expression was identified among examined sarcomas. To our knowledge, this is the first immunohistochemistry study to report the frequency and pattern of GITR expression in a large breast cancer cohort, or to report membranous GITR expression on malignant cells. The co-infiltration of GITR with other immune biomarkers and T-cell markers supports a potential role for anti-GITR agents in combination immunotherapies. In addition, GITR expression on carcinoma cells could imply the existence of a novel cancer immune evasion strategy worthy of further investigation.
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Affiliation(s)
- Mayanne M T Zhu
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada
| | - Samantha Burugu
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada
| | - Dongxia Gao
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada
| | - Jamie Yu
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Zuzana Kos
- Department of Pathology, BC Cancer, Vancouver, BC, Canada
| | - Samuel Leung
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada
| | - Basil A Horst
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Torsten O Nielsen
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada. .,Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
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35
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Flerin NC, Pinioti S, Menga A, Castegna A, Mazzone M. Impact of Immunometabolism on Cancer Metastasis: A Focus on T Cells and Macrophages. Cold Spring Harb Perspect Med 2020; 10:a037044. [PMID: 31615868 PMCID: PMC7461771 DOI: 10.1101/cshperspect.a037044] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite improved treatment options, cancer remains the leading cause of morbidity and mortality worldwide, with 90% of this mortality correlated to the development of metastasis. Since metastasis has such an impact on treatment success, disease outcome, and global health, it is important to understand the different steps and factors playing key roles in this process, how these factors relate to immune cell function and how we can target metabolic processes at different steps of metastasis in order to improve cancer treatment and patient prognosis. Recent insights in immunometabolism direct to promising therapeutic targets for cancer treatment, however, the specific contribution of metabolism on antitumor immunity in different metastatic niches warrant further investigation. Here, we provide an overview of what is so far known in the field of immunometabolism at different steps of the metastatic cascade, and what may represent the next steps forward. Focusing on metabolic checkpoints in order to translate these findings from in vitro and mouse studies to the clinic has the potential to revolutionize cancer immunotherapy and greatly improve patient prognosis.
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Affiliation(s)
- Nina C Flerin
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Sotiria Pinioti
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Alessio Menga
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Alessandra Castegna
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari 70125, Italy
- IBIOM-CNR, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Italy
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
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36
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Ngiow SF, Young A. Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies. Front Immunol 2020; 11:1633. [PMID: 32849557 PMCID: PMC7399169 DOI: 10.3389/fimmu.2020.01633] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/18/2020] [Indexed: 12/16/2022] Open
Abstract
The clinical success of cancer immunotherapies targeting PD-1 and CTLA-4 has ignited a substantial research effort to improve our understanding of tumor immunity. Recent studies have revealed that the immune contexture of a tumor influences therapeutic response and survival benefit for cancer patients. Identifying treatment modalities that limit immunosuppression, relieve T cell exhaustion, and potentiate effector functions in the tumor microenvironment (TME) is of much interest. In particular, combinatorial therapeutic approaches that re-educate the TME by limiting the accumulation of immunosuppressive immune cells, such as Foxp3 regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), while promoting CD8+ and CD4+ effector T cell activity is critical. Here, we review key approaches to target these immunosuppressive immune cell subsets and signaling molecules and define the impact of these changes to the tumor milieu. We will highlight the preclinical and clinical evidence for their ability to improve anti-tumor immune responses as well as strategies and challenges for their implementation. Together, this review will provide understanding of therapeutic approaches to efficiently shape the TME and reinvigorate the immune response against cancer.
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Affiliation(s)
- Shin Foong Ngiow
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Arabella Young
- Department of Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
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37
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Rocco D, Gregorc V, Della Gravara L, Lazzari C, Palazzolo G, Gridelli C. New immunotherapeutic drugs in advanced non-small cell lung cancer (NSCLC): from preclinical to phase I clinical trials. Expert Opin Investig Drugs 2020; 29:1005-1023. [PMID: 32643447 DOI: 10.1080/13543784.2020.1793956] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The development of immune checkpoint inhibitors (ICI) has represented a revolution in the treatment of non-small cell lung cancer (NSCLC) and has established a new standard of care for different settings. However, through adaptive changes, cancer cells can develop resistance mechanisms to these drugs, hence the necessity for novel immunotherapeutic agents. AREAS COVERED This paper explores the immunotherapeutics currently under investigation in phase I clinical trials for the treatment of NSCLC as monotherapies and combination therapies. It provides two comprehensive tables of phase I agents which are listed according to target, drug, drug class, mechanism of action, setting, trial identifier, and trial status. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov. EXPERT OPINION A key hurdle to success in this field is our limited understanding of the synergic interactions of the immune targets in the context of the TME. While we can recognize the links between inhibitors and some particularly promising new targets such as TIM-3 and LAG3, we continue to develop approaches to exploit their interactions to enhance the immune response of the patient to tumor cells.
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Affiliation(s)
- Danilo Rocco
- Department of Pulmonary Oncology, AORN Dei Colli Monaldi , Naples, Italy
| | - Vanesa Gregorc
- Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele , Milan, Italy
| | - Luigi Della Gravara
- Department of Experimental Medicine, Università Degli Studi Della Campania "Luigi Vanvitelli" , Caserta, Italy
| | - Chiara Lazzari
- Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele , Milan, Italy
| | | | - Cesare Gridelli
- Division of Medical Oncology, "S.G. Moscati" Hospital , Avellino, Italy
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38
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Guo Q, Zhang Z, Zhao P, Zou S, Li L, Li N, Sun W, Wei X, Hou L, Yang Z, Gao D. Bispecific antibody activated T cells: A newly developed T cells with enhanced proliferation ability and cytotoxicity. Immunol Lett 2020; 220:79-87. [DOI: 10.1016/j.imlet.2019.12.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 12/12/2019] [Accepted: 12/30/2019] [Indexed: 01/07/2023]
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39
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Yang Y, Nam GH, Kim GB, Kim YK, Kim IS. Intrinsic cancer vaccination. Adv Drug Deliv Rev 2019; 151-152:2-22. [PMID: 31132376 DOI: 10.1016/j.addr.2019.05.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 12/15/2022]
Abstract
Immunotherapy is revolutionizing the treatment of cancer, and the current immunotherapeutics have remarkably improved the outcomes for some cancer patients. However, we still need answers for patients with immunologically cold tumors that do not benefit from the current immunotherapy treatments. Here, we suggest a novel strategy that is based on using a very old and sophisticated system for cancer immunotherapy, namely "intrinsic cancer vaccination", which seeks to awaken our own immune system to activate tumor-specific T cells. To do this, we must take advantage of the genetic instability of cancer cells and the expression of cancer cell neoantigens to trigger immunity against cancer cells. It will be necessary to not only enhance the phagocytosis of cancer cells by antigen presenting cells but also induce immunogenic cancer cell death and the subsequent immunogenic clearance, cross-priming and generation of tumor-specific T cells. This strategy will allow us to avoid using known tumor-specific antigens, ex vivo manipulation or adoptive cell therapy; rather, we will efficiently present cancer cell neoantigens to our immune system and propagate the cancer-immunity cycle. This strategy simply follows the natural cycle of cancer-immunity from its very first step, and therefore could be combined with any other treatment modality to yield enhanced efficacy.
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Affiliation(s)
- Yoosoo Yang
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Gi-Hoon Nam
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Gi Beom Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Yoon Kyoung Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - In-San Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
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40
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Sanseviero E. NK Cell-Fc Receptors Advance Tumor Immunotherapy. J Clin Med 2019; 8:E1667. [PMID: 31614774 PMCID: PMC6832859 DOI: 10.3390/jcm8101667] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy has revolutionized the treatment of cancer patients. Among immunotherapeutic approaches, antibodies targeting immune checkpoint inhibitors Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for treatment of metastatic melanoma and are in clinical trials for a variety of other cancers. The contribution of Natural Killer (NK) cells to the efficacy of immune checkpoint inhibitors is becoming more evident. Enhancing both T and NK cell function in cancer could result in a robust and durable response. Along with the ability to directly kill tumor cells, NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) given the expression of Fragment Crystallizable (Fc) receptors. Promising novel antibodies modified with improved Fc-receptor-mediated functions or Fc-engagers to kill target cells have been tested in pre-clinical models with considerable results. Combination therapies with immune-therapeutic antibodies with enhancers of NK-cell Fc-receptor-mediated function can be exploited to increase the efficacy of these antibodies. Herein, I discuss possible strategies to improve the success of immunotherapy by boosting NK cell function.
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Affiliation(s)
- Emilio Sanseviero
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
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41
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Vence L, Bucktrout SL, Fernandez Curbelo I, Blando J, Smith BM, Mahne AE, Lin JC, Park T, Pascua E, Sai T, Chaparro-Riggers J, Subudhi SK, Scutti JB, Higa MG, Zhao H, Yadav SS, Maitra A, Wistuba II, Allison JP, Sharma P. Characterization and Comparison of GITR Expression in Solid Tumors. Clin Cancer Res 2019; 25:6501-6510. [PMID: 31358539 DOI: 10.1158/1078-0432.ccr-19-0289] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/16/2019] [Accepted: 07/11/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize the tumor microenvironment for the frequency of GITR expression in T-cell subsets from seven different human solid tumors.Experimental Design: For mouse experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single-cell level using flow cytometry (FC). A total of 213 samples were evaluated for GITR expression by IHC, 63 by FC, and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. RESULTS The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that NSCLC, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4+ Foxp3+ T regulatory cells. IHC and FC data showed similar trends with a good correlation between both techniques. CONCLUSIONS Human tumor data suggest that NSCLC, renal cell carcinoma, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.
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Affiliation(s)
- Luis Vence
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Samantha L Bucktrout
- Cancer Immunology Discovery Unit, South San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco, California
| | - Irina Fernandez Curbelo
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jorge Blando
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bevin M Smith
- Cancer Immunology Discovery Unit, South San Francisco, California
| | - Ashley E Mahne
- Cancer Immunology Discovery Unit, South San Francisco, California
| | - John C Lin
- Cancer Immunology Discovery Unit, South San Francisco, California.,Regeneron Pharmaceuticals Inc., Tarrytown, New York
| | - Terrence Park
- Cancer Immunology Discovery Unit, South San Francisco, California
| | - Edward Pascua
- Cancer Immunology Discovery Unit, South San Francisco, California
| | - Tao Sai
- Cancer Immunology Discovery Unit, South San Francisco, California
| | | | - Sumit K Subudhi
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jorge B Scutti
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria G Higa
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hao Zhao
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shalini S Yadav
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anirban Maitra
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - James P Allison
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Padmanee Sharma
- The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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42
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Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M. The Evolving Role of CD8 +CD28 - Immunosenescent T Cells in Cancer Immunology. Int J Mol Sci 2019; 20:ijms20112810. [PMID: 31181772 PMCID: PMC6600236 DOI: 10.3390/ijms20112810] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/05/2019] [Accepted: 06/06/2019] [Indexed: 12/18/2022] Open
Abstract
Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.
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Affiliation(s)
- Wei X Huff
- Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Jae Hyun Kwon
- Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Mario Henriquez
- Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Kaleigh Fetcko
- Department of Neurology, University of Illinois at Chicago School of Medicine, Chicago, IL 60612, USA.
| | - Mahua Dey
- Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Expression of costimulatory and inhibitory receptors in FoxP3 + regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches. Adv Cancer Res 2019; 144:193-261. [PMID: 31349899 DOI: 10.1016/bs.acr.2019.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.
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Abstract
With the advent of the concept of dominant tolerance and the subsequent discovery of CD4+ regulatory T cells expressing the transcription factor FOXP3 (Tregs), almost all productive as well as nonproductive immune responses can be compartmentalized to a binary of immune effector T cells and immune regulatory Treg populations. A beneficial immune response warrants the timely regulation by Tregs, whereas a nonproductive immune response indicates insufficient effector functions or an outright failure of tolerance. There are ample reports supporting role of Tregs in suppressing spontaneous auto-immune diseases as well as promoting immune evasion by cancers. To top up their importance, several non-immune functions like tissue homeostasis and regeneration are also being attributed to Tregs. Hence, after being in the center stage of basic and translational immunological research, Tregs are making the next jump towards clinical studies. Therefore, newer small molecules, biologics as well as adoptive cell therapy (ACT) approaches are being tested to augment or undermine Treg responses in the context of autoimmunity and cancer. In this brief review, we present the strategies to modulate Tregs towards a favorable clinical outcome.
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Affiliation(s)
- Amit Sharma
- Academy of Immunology and Microbiology, Institute for Basic Science (IBS) , Pohang , Republic of Korea.,Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology (POSTECH) , Pohang , Republic of Korea
| | - Dipayan Rudra
- Academy of Immunology and Microbiology, Institute for Basic Science (IBS) , Pohang , Republic of Korea.,Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology (POSTECH) , Pohang , Republic of Korea
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45
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Spagnuolo A, Gridelli C. Combining immunotherapies to treat non-small cell lung cancer. Expert Rev Respir Med 2019; 13:621-634. [PMID: 31116072 DOI: 10.1080/17476348.2019.1623027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Introduction: In recent years, immunotherapy has become an integral part of the treatment of many cancers, including non-small cell lung cancer (NSCLC). Precious therapeutic weapons impacting survival are monoclonal antibodies directed against the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint. Areas covered: Unfortunately, not all patients treated with checkpoint inhibitors have durable clinical responses. However, a better understanding of the complexity of interactions between the immune system and cancer, the latter capable of adopting evasion mechanisms, indicates different opportunities to enhance anti-tumor immunity. Expert opinion: In this paper, we review multiple strategies of combining immunotherapies that exploit not only additional immune checkpoint receptors and ligands but also other synergistic approaches such as vaccines or indoleamine 2,3-dioxygenase (IDO) inhibitors with the potential to extend the number of NSCLC patients achieving successful outcomes.
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Affiliation(s)
- Alessia Spagnuolo
- a Division of Medical Oncology , 'S. G. Moscati' Hospital , Avellino , Italy
| | - Cesare Gridelli
- a Division of Medical Oncology , 'S. G. Moscati' Hospital , Avellino , Italy
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46
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Chrétien S, Zerdes I, Bergh J, Matikas A, Foukakis T. Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy. Cancers (Basel) 2019; 11:E628. [PMID: 31060337 PMCID: PMC6562626 DOI: 10.3390/cancers11050628] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor - host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.
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Affiliation(s)
- Sebastian Chrétien
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Ioannis Zerdes
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Jonas Bergh
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Alexios Matikas
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Theodoros Foukakis
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
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47
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León-Letelier RA, Bonifaz LC, Fuentes-Pananá EM. OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy. J Leukoc Biol 2019; 105:915-933. [PMID: 30698862 DOI: 10.1002/jlb.mr0618-241rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/24/2018] [Accepted: 12/29/2018] [Indexed: 12/15/2022] Open
Abstract
Melanoma is the deadliest form of skin cancer. Cutaneous melanomas usually originate from exposure to the mutagenic effects of ultraviolet radiation, and as such they exhibit the highest rate of somatic mutations than any other human cancer, and an extensive expression of neoantigens concurrently with a dense infiltrate of immune cells. The coexistence of high immunogenicity and high immune cell infiltration may sound contradictory for cancers carrying a gloomy outcome. However, recent studies have unveiled a variety of immunosuppressive mechanisms that often permeate the tumor microenvironment and that are responsible for tumor escaping from immunosurveillance mechanisms. Nonetheless, this particular immune profile has opened a new window of treatments based on immunotherapy that have significantly improved the clinical outcome of melanoma patients. Still, positive and complete therapy responses have been limited, and this particular cancer continues to be a major clinical challenge. The transcriptomic signatures of those patients with clinical benefit and those with progressive disease have provided a more complete picture of the universe of interactions between the tumor and the immune system. In this review, we integrate the results of the immunotherapy clinical trials to discuss a novel understanding of the mechanisms guiding cancer immunosurveillance and immunoediting. A clear notion of the cellular and molecular processes shaping how the immune system and the tumor are continuously coevolving would result in the rational design of combinatory therapies aiming to counteract the signaling pathways and cellular processes responsible for immunoescape mechanisms and provide clinical benefit to immunotherapy nonresponsive patients.
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Affiliation(s)
- Ricardo A León-Letelier
- Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, México
- Universidad Nacional Autónoma de México (UNAM), México Ciudad de México, México
| | - Laura C Bonifaz
- Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, México
| | - Ezequiel M Fuentes-Pananá
- Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Ciudad de México, México
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48
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Han S, Toker A, Liu ZQ, Ohashi PS. Turning the Tide Against Regulatory T Cells. Front Oncol 2019; 9:279. [PMID: 31058083 PMCID: PMC6477083 DOI: 10.3389/fonc.2019.00279] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/26/2019] [Indexed: 12/11/2022] Open
Abstract
Regulatory T (Treg) cells play crucial roles in health and disease through their immunosuppressive properties against various immune cells. In this review we will focus on the inhibitory role of Treg cells in anti-tumor immunity. We outline how Treg cells restrict T cell function based on our understanding of T cell biology, and how we can shift the equilibrium against regulatory T cells. To date, numerous strategies have been proposed to limit the suppressive effects of Treg cells, including Treg cell neutralization, destabilizing Treg cells and rendering T cells resistant to Treg cells. Here, we focus on key mechanisms which render T cells resistant to the suppressive effects of Treg cells. Lastly, we also examine current limitations and caveats of overcoming the inhibitory activity of Treg cells, and briefly discuss the potential to target Treg cell resistance in the context of anti-tumor immunity.
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Affiliation(s)
- SeongJun Han
- Princess Margaret Cancer Centre, Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Aras Toker
- Princess Margaret Cancer Centre, Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada
| | - Zhe Qi Liu
- Princess Margaret Cancer Centre, Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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Medler J, Wajant H. Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. Expert Opin Ther Targets 2019; 23:295-307. [PMID: 30856027 DOI: 10.1080/14728222.2019.1586886] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Tumor necrosis factor (TNF) receptor 2 (TNFR2) is one of two receptors of the cytokines, TNF and lymphotoxin-α. TNFR1 is a strong inducer of proinflammatory activities. TNFR2 has proinflammatory effects too, but it also elicits strong anti-inflammatory activities and has protective effects on oligodendrocytes, cardiomyocytes, and keratinocytes. The protective and anti-inflammatory effects of TNFR2 may explain why TNF inhibitors failed to be effective in diseases such as heart failure or multiple sclerosis, where TNF has been strongly implicated as a driving force. Stimulatory and inhibitory TNFR2 targeting hence attracts considerable interest for the treatment of autoimmune diseases and cancer. Areas covered: Based on a brief description of the pathophysiological importance of the TNF-TNFR1/2 system, we discuss the potential applications of TNFR2 targeting therapies. We also debate TNFR2 activation as a way forward in the search for TNFR2-specific agents. Expert opinion: The use of TNFR2 to target regulatory T-cells is attractive, but this approach is just one amongst many suitable targets. With respect to its preference for Treg stimulation and protection of non-immune cells, TNFR2 is more unique and thus offers opportunities for translational success.
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Affiliation(s)
- Juliane Medler
- a Division for Molecular Internal Medicine, Department of Internal Medicine II , University Hospital Würzburg , Würzburg , Germany
| | - Harald Wajant
- a Division for Molecular Internal Medicine, Department of Internal Medicine II , University Hospital Würzburg , Würzburg , Germany
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50
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Onda M, Kobayashi K, Pastan I. Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity. Proc Natl Acad Sci U S A 2019; 116:4575-4582. [PMID: 30760587 PMCID: PMC6410866 DOI: 10.1073/pnas.1820388116] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The tumor microenvironment plays a critical role in controlling tumor progression and immune surveillance. We produced an immunotoxin (2E4-PE38) that kills mouse cells expressing CD25 by attaching the Fv portion of monoclonal antibody 2E4 (anti-mouse CD25) to a 38-kDa portion of Pseudomonas exotoxin A. We employed three mouse cancer tumor models (AB1 mesothelioma, 66c14 breast cancer, and CT26M colon cancer). Tumors were implanted at two sites on BALB/c mice. On days 5 and 9, one tumor was directly injected with 2E4-PE38, and the other was not treated; 2E4-PE38 produced complete regressions of 85% of injected AB1 tumors, 100% of 66c14 tumors, and 100% of CT26M tumors. It also produced complete regressions of 77% of uninjected AB1 tumors, 47% of 66c14 tumors, and 92% of CT26M tumors. Mice with complete regressions of 66c14 tumors were immune to rechallenge with 66c14 cells. Mice with complete regressions of AB1 or CT26M tumors developed cross-tumor immunity rejecting both tumor types. Injection of anti-CD25 antibody or a mutant inactive immunotoxin were generally ineffective. Tumors were analyzed 3 days after 2E4-PE38 injection. The number of regulatory T cells (Tregs) was significantly reduced in the injected tumor but not in the spleen. Injected tumors contained an increase in CD8 T cells expressing IFN-γ, the activation markers CD69 and CD25, and macrophages and conventional dendritic cells. Treatment with antibodies to CD8 abolished the antitumor effect. Selective depletion of Tregs in tumors facilitates the development of a CD8 T cell-dependent antitumor effect in three mouse models.
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Affiliation(s)
- Masanori Onda
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
| | - Kazuto Kobayashi
- Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
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