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1
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Guia S, Fenis A, Baudesson De Chanville C, Galluso J, Medjouel H, Escaliere B, Modelska A, Vienne M, Lopes N, Pouchin A, Rossi B, Gauthier L, Roulland S, Vivier E, Narni-Mancinelli E. Genome-wide CRISPR/Cas9 screen reveals factors that influence the susceptibility of tumor cells to NK cell-mediated killing. J Immunother Cancer 2025; 13:e010699. [PMID: 40164474 PMCID: PMC11962812 DOI: 10.1136/jitc-2024-010699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/17/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Natural killer (NK) cells exhibit potent cytotoxic activity against various cancer cell types. Over the past five decades, numerous methodologies have been employed to elucidate the intricate molecular mechanisms underlying NK cell-mediated tumor control. While significant progress has been made in elucidating the interactions between NK cells and tumor cells, the regulatory factors governing NK cell-mediated tumor cell destruction are not yet fully understood. This includes the diverse array of tumor ligands recognized by NK cells and the mechanisms that NK cells employ to eliminate tumor cells. METHODS In this study, we employed a genome-wide CRISPR/Cas9 screening approach in conjunction with functional cytotoxicity assays to delineate the pathways modulating the susceptibility of colon adenocarcinoma HCT-116 cells to NK cell-mediated cytotoxicity. RESULTS Analysis of guide RNA distribution in HCT-116 cells that survived co-incubation with NK cells identified ICAM-1 as a pivotal player in the NKp44-mediated immune synapse, with NKp44 serving as an activating receptor crucial for the elimination of HCT-116 tumor cells by NK cells. Furthermore, disruption of genes involved in the apoptosis or interferon (IFN)-γ signaling pathways conferred resistance to NK cell attack. We further dissected that NK cell-derived IFN-γ promotes mitochondrial apoptosis in vitro and exerts control over B16-F10 lung metastases in vivo. CONCLUSION Monitoring ICAM-1 levels on the surface of tumor cells or modulating its expression should be considered in the context of NK cell-based therapy. Furthermore, promoting FasL expression on the NK cell surface is reaffirmed as an important strategy to enhance NK cell-mediated tumor killing, offering an additional avenue for therapeutic optimization. Additionally, considering the diffusion properties of IFN-γ, our findings highlight the potential of leveraging NK cell-derived IFN-γ to enhance direct tumor cell killing and facilitate bystander effects via cytokine diffusion, warranting further investigation.
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Affiliation(s)
- Sophie Guia
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Aurore Fenis
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
- Innate Pharma SA, Marseille, France
| | | | | | - Hakim Medjouel
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Bertrand Escaliere
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Angelika Modelska
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Margaux Vienne
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Noella Lopes
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Amelie Pouchin
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | | | | | - Sandrine Roulland
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
| | - Eric Vivier
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
- Innate Pharma SA, Marseille, France
| | - Emilie Narni-Mancinelli
- CIML, Marseille, France
- Aix-Marseille-University, Marseille, France
- U1104, INSERM, Marseille, France
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2
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Melo Garcia L, Gangadharan A, Banerjee P, Li Y, Zeng AGX, Rafei H, Lin P, Kumar B, Acharya S, Daher M, Muniz-Feliciano L, Deyter GM, Dominguez G, Park JM, Reyes Silva F, Nunez Cortes AK, Basar R, Uprety N, Shanley M, Kaplan M, Liu E, Shpall EJ, Rezvani K. Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells. Cell Rep 2025; 44:115122. [PMID: 39754720 PMCID: PMC11838179 DOI: 10.1016/j.celrep.2024.115122] [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: 05/29/2024] [Revised: 10/26/2024] [Accepted: 12/06/2024] [Indexed: 01/06/2025] Open
Abstract
CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.
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MESH Headings
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/pathology
- T Lineage-Specific Activation Antigen 1
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Antigens, Differentiation, T-Lymphocyte/genetics
- Antigens, Differentiation, T-Lymphocyte/immunology
- Receptors, Chimeric Antigen/metabolism
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Lymphocyte Function-Associated Antigen-1/metabolism
- Immune Evasion
- Cell Line, Tumor
- Immunological Synapses/immunology
- Female
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Affiliation(s)
- Luciana Melo Garcia
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; Hematology-Oncology Service, CHU de Québec - Université Laval, Quebec City, QC G1V 0A6, Canada
| | - Achintyan Gangadharan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33616, USA
| | - Pinaki Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Andy G X Zeng
- Princess Margaret Cancer Center, University Healthy Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Hind Rafei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bijender Kumar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gary M Deyter
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Dominguez
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jeong Min Park
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Francia Reyes Silva
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ana Karen Nunez Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mecit Kaplan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Huang X, Pawge G, Snicer CE, Hsiao CHC, Wiemer AJ. PVR exposure influences the activation, adhesion, and protein expression of human CD8+ T cells, including the CD96-mediated transfer of PVR. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:55-71. [PMID: 40073261 DOI: 10.1093/jimmun/vkae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/23/2024] [Indexed: 03/14/2025]
Abstract
Poliovirus receptor (PVR) ligands have gained attention as immunotherapy targets, yet their regulation remains unclear. Here, we examine the impact of PVR exposure on primary human CD8+ T cells. We used flow cytometry and Western blot analysis to quantify expression of PVR and its ligands in naïve and effector T cells and used adhesion assays and enzyme-linked immunosorbent assay (ELISA) to assess the impact of PVR on T cell adhesion and cytokine production. Stimulation with phytohemagglutinin P strongly increased DNAM-1 expression and caused a less robust and more variable increase in TIGIT expression. Exposure to PVR-Fc enhanced the CD8+ T cell adhesion to ICAM-1-coated plates in a dose-dependent manner, while exposure to PVR-expressing K32 cells mildly decreased CD8+ T cell interferon γ release. However, PVR exposure strongly decreased the expression of DNAM-1, TIGIT, and CD96. The reduction of DNAM-1, TIGIT, and CD96 induced by PVR was dominant to the increase caused by T cell receptor signaling. The impact of PVR on their expression was completely abolished by the Q63R and F128R point mutations of PVR, while DNAM-1 was partially rescued by inhibitors of Src and protein kinase C. Additionally, PVR exposure along with T cell receptor signaling promoted the transfer of surface proteins including PVR from K32 cells to CD8+ T cells. This PVR transfer was mediated by the IgV domain of PVR and CD96 on CD8+ T cells and required cellular contact. Our findings collectively demonstrate that PVR engagement has a mild antagonistic effect on interferon γ production but strongly impacts CD8+ T cell adhesion and protein expression.
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MESH Headings
- Humans
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Cell Adhesion/immunology
- Lymphocyte Activation/immunology
- Receptors, Virus/metabolism
- Receptors, Virus/immunology
- Receptors, Virus/genetics
- T Lineage-Specific Activation Antigen 1
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Antigens, Differentiation, T-Lymphocyte/immunology
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/immunology
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Interferon-gamma/metabolism
- Cells, Cultured
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Affiliation(s)
- Xueting Huang
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
| | - Girija Pawge
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
| | - Christina E Snicer
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
| | | | - Andrew J Wiemer
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
- Institute for Systems Genomics, University of Connecticut, Storrs, CT, United States
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4
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Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther 2024; 9:302. [PMID: 39511139 PMCID: PMC11544004 DOI: 10.1038/s41392-024-02005-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 11/15/2024] Open
Abstract
Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56dim and CD56bright NK cells execute cytotoxicity, while CD56bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells' functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.
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Affiliation(s)
- Sumei Chen
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
| | - Haitao Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Youssef Jounaidi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Morandi E, Adoue V, Bernard I, Friebel E, Nunez N, Aubert Y, Masson F, Dejean AS, Becher B, Astier A, Martinet L, Saoudi A. Impact of the Multiple Sclerosis-Associated Genetic Variant CD226 Gly307Ser on Human CD8 T-Cell Functions. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2024; 11:e200306. [PMID: 39231385 PMCID: PMC11379124 DOI: 10.1212/nxi.0000000000200306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/08/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND AND OBJECTIVES The rs763361 nonsynonymous variant in the CD226 gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined. METHODS To study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production. RESULTS On TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ. DISCUSSION Our data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.
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Affiliation(s)
- Elena Morandi
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Véronique Adoue
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Isabelle Bernard
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Ekaterina Friebel
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Nicolas Nunez
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Yann Aubert
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Frederick Masson
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Anne S Dejean
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Burkhard Becher
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Anne Astier
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Ludovic Martinet
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Abdelhadi Saoudi
- From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
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Jo Y, Sim HI, Yun B, Park Y, Jin HS. Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2. Exp Mol Med 2024; 56:2113-2126. [PMID: 39349829 PMCID: PMC11541569 DOI: 10.1038/s12276-024-01317-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/26/2024] [Accepted: 07/04/2024] [Indexed: 10/03/2024] Open
Abstract
Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy.
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Affiliation(s)
- Yunju Jo
- Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea
| | - Hye-In Sim
- Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea
| | - Bohwan Yun
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoon Park
- Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
| | - Hyung-Seung Jin
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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Piovesan D, de Groot AE, Cho S, Anderson AE, Ray RD, Patnaik A, Foster PG, Mitchell CG, Lopez Espinoza AY, Zhu WS, Stagnaro CE, Singh H, Zhao X, Seitz L, Walker NP, Walters MJ, Sivick KE. Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells. Cancer Res 2024; 84:1978-1995. [PMID: 38635895 DOI: 10.1158/0008-5472.can-23-2455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 02/02/2024] [Accepted: 04/02/2024] [Indexed: 04/20/2024]
Abstract
T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.
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8
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Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells 2024; 13:941. [PMID: 38891073 PMCID: PMC11172350 DOI: 10.3390/cells13110941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/18/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Regulatory T cells (Tregs) are essential to maintain immune homeostasis by promoting self-tolerance. Reduced Treg numbers or functionality can lead to a loss of tolerance, increasing the risk of developing autoimmune diseases. An overwhelming variety of human Tregs has been described, based on either specific phenotype, tissue compartment, or pathological condition, yet the bulk of the literature only addresses CD25-positive and CD127-negative cells, coined by naturally occurring Tregs (nTregs), most of which express the transcription factor Forkhead box protein 3 (FOXP3). While the discovery of FOXP3 was seminal to understanding the origin and biology of nTregs, there is evidence in humans that not all T cells expressing FOXP3 are regulatory, and that not all Tregs express FOXP3. Namely, the activation of human T cells induces the transient expression of FOXP3, irrespective of whether they are regulatory or inflammatory effectors, while some induced T cells that may be broadly defined as Tregs (e.g., Tr1 cells) typically lack demethylation and do not express FOXP3. Furthermore, it is unknown whether and how many nTregs exist without FOXP3 expression. Several other candidate regulatory molecules, such as GITR, Lag-3, GARP, GPA33, Helios, and Neuropilin, have been identified but subsequently discarded as Treg-specific markers. Multiparametric analyses have uncovered a plethora of Treg phenotypes, and neither single markers nor combinations thereof can define all and only Tregs. To date, only the functional capacity to inhibit immune responses defines a Treg and distinguishes Tregs from inflammatory T cells (Teffs) in humans. This review revisits current knowledge of the Treg universe with respect to their heterogeneity in phenotype and function. We propose that it is unavoidable to characterize human Tregs by their phenotype in combination with their function, since phenotype alone does not unambiguously define Tregs. There is an unmet need to align the expression of specific markers or combinations thereof with a particular suppressive function to coin functional Treg entities and categorize Treg diversity.
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Affiliation(s)
- Chelsea Gootjes
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (J.J.Z.); (T.N.)
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9
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Sakano Y, Sakano K, Hurrell BP, Helou DG, Shafiei-Jahani P, Kazemi MH, Li X, Shen S, Hilser JR, Hartiala JA, Allayee H, Barbers R, Akbari O. Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity. J Allergy Clin Immunol 2024; 153:1406-1422.e6. [PMID: 38244725 DOI: 10.1016/j.jaci.2024.01.003] [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: 08/25/2023] [Revised: 12/19/2023] [Accepted: 01/03/2024] [Indexed: 01/22/2024]
Abstract
BACKGROUND Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases. OBJECTIVE We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR). METHODS We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2-/- mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s. RESULTS Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls. CONCLUSION Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
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Affiliation(s)
- Yoshihiro Sakano
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Kei Sakano
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Benjamin P Hurrell
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Doumet Georges Helou
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Pedram Shafiei-Jahani
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Mohammad H Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Xin Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Stephen Shen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - James R Hilser
- Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Jaana A Hartiala
- Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Hooman Allayee
- Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Richard Barbers
- Department of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, Calif
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif.
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10
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Lacouture C, Chaves B, Guipouy D, Houmadi R, Duplan-Eche V, Allart S, Destainville N, Dupré L. LFA-1 nanoclusters integrate TCR stimulation strength to tune T-cell cytotoxic activity. Nat Commun 2024; 15:407. [PMID: 38195629 PMCID: PMC10776856 DOI: 10.1038/s41467-024-44688-3] [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: 02/05/2023] [Accepted: 12/29/2023] [Indexed: 01/11/2024] Open
Abstract
T-cell cytotoxic function relies on the cooperation between the highly specific but poorly adhesive T-cell receptor (TCR) and the integrin LFA-1. How LFA-1-mediated adhesion may scale with TCR stimulation strength is ill-defined. Here, we show that LFA-1 conformation activation scales with TCR stimulation to calibrate human T-cell cytotoxicity. Super-resolution microscopy analysis reveals that >1000 LFA-1 nanoclusters provide a discretized platform at the immunological synapse to translate TCR engagement and density of the LFA-1 ligand ICAM-1 into graded adhesion. Indeed, the number of high-affinity conformation LFA-1 nanoclusters increases as a function of TCR triggering strength. Blockade of LFA-1 conformational activation impairs adhesion to target cells and killing. However, it occurs at a lower TCR stimulation threshold than lytic granule exocytosis implying that it licenses, rather than directly controls, the killing decision. We conclude that the organization of LFA-1 into nanoclusters provides a calibrated system to adjust T-cell killing to the antigen stimulation strength.
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Affiliation(s)
- Claire Lacouture
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
- Laboratoire de Physique Théorique, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Beatriz Chaves
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
- National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
- Computational Modeling Group, Oswaldo Cruz Foundation (Fiocruz), Eusébio, Brazil
| | - Delphine Guipouy
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
| | - Raïssa Houmadi
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
| | - Valérie Duplan-Eche
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
| | - Sophie Allart
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
| | - Nicolas Destainville
- Laboratoire de Physique Théorique, Université de Toulouse, CNRS, UPS, Toulouse, France.
| | - Loïc Dupré
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France.
- Department of Dermatology, Medical University of Vienna, Vienna, Austria.
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11
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Zhou R, Chen S, Wu Q, Liu L, Wang Y, Mo Y, Zeng Z, Zu X, Xiong W, Wang F. CD155 and its receptors in cancer immune escape and immunotherapy. Cancer Lett 2023; 573:216381. [PMID: 37660884 DOI: 10.1016/j.canlet.2023.216381] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/15/2023] [Accepted: 08/31/2023] [Indexed: 09/05/2023]
Abstract
In recent years, there have been multiple breakthroughs in cancer immunotherapy, with immune checkpoint inhibitors becoming the most promising treatment strategy. However, available drugs are not always effective. As an emerging immune checkpoint molecule, CD155 has become an important target for immunotherapy. This review describes the structure and function of CD155, its receptors TIGIT, CD96, and CD226, and summarizes that CD155 expressed by tumor cells can upregulate its expression through the DNA damage response pathway and Ras-Raf-MEK-ERK signaling pathway. This review also elaborates the mechanism of immune escape after binding CD155 to its receptors TIGIT, CD96, and CD226, and summarizes the current progress of immunotherapy research regarding CD155 and its receptors. Besides, it also discusses the future direction of checkpoint immunotherapy.
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Affiliation(s)
- Ruijia Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shiyin Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiwen Wu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lingyun Liu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - Yian Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yongzhen Mo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Fuyan Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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12
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Paolini R, Molfetta R. Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment. Cancers (Basel) 2023; 15:4616. [PMID: 37760586 PMCID: PMC10527063 DOI: 10.3390/cancers15184616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/10/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
NK cells play a pivotal role in anti-cancer immune responses, thanks to the expression of a wide array of inhibitory and activating receptors that regulate their cytotoxicity against transformed cells while preserving healthy cells from lysis. However, NK cells exhibit severe dysfunction in the tumor microenvironment, mainly due to the reduction of activating receptors and the induction or increased expression of inhibitory checkpoint receptors. An activating receptor that plays a central role in tumor recognition is the DNAM-1 receptor. It recognizes PVR and Nectin2 adhesion molecules, which are frequently overexpressed on the surface of cancerous cells. These ligands are also able to trigger inhibitory signals via immune checkpoint receptors that are upregulated in the tumor microenvironment and can counteract DNAM-1 activation. Among them, TIGIT has recently gained significant attention, since its targeting results in improved anti-tumor immune responses. This review aims to summarize how the recognition of PVR and Nectin2 by paired co-stimulatory/inhibitory receptors regulates NK cell-mediated clearance of transformed cells. Therapeutic approaches with the potential to reverse DNAM-1 dysfunction in the tumor microenvironment will be also discussed.
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Affiliation(s)
| | - Rosa Molfetta
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy;
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13
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Matsuo S, Nabekura T, Matsuda K, Shibuya K, Shibuya A. DNAM-1 Immunoreceptor Protects Mice from Concanavalin A-Induced Acute Liver Injury by Reducing Neutrophil Infiltration. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:954-963. [PMID: 37522739 DOI: 10.4049/jimmunol.2200705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 07/13/2023] [Indexed: 08/01/2023]
Abstract
DNAX accessory molecule-1 (DNAM-1; CD226) is an activating immunoreceptor on T cells and NK cells. The interaction of DNAM-1 with its ligand CD155 expressed on hematopoietic and nonhematopoietic cells plays an important role in innate and adaptive immune responses. In this study, we investigated the role of the DNAM-1-CD155 axis in the pathogenesis of T cell-mediated Con A-induced acute liver injury. Unexpectedly, DNAM-1-deficient (Cd226-/-) mice exhibited more severe acute liver injury and higher concentrations of IL-6 and TNF-α than did wild-type (WT) mice after Con A injection. We found that a larger number of neutrophils infiltrated into the liver of Cd226-/- mice compared with WT mice after Con A injection. Depletion of neutrophils ameliorated liver injury and decreased IL-6 and TNF-α in Cd226-/- mice after Con A injection, suggesting that neutrophils exacerbate the liver injury in Cd226-/- mice. Hepatocytes produced more significant amounts of CXCL1, a chemoattractant for neutrophils, in Cd226-/- mice than in WT mice after Con A injection. In the coculture of hepatocytes with liver lymphocytes, either DNAM-1 deficiency in liver lymphocytes or CD155 deficiency in hepatocytes promoted CXCL1 production by hepatocytes. These results suggest that the interaction of DNAM-1 with CD155 inhibits CXCL1 production by hepatocytes, leading to ameliorating acute liver injury.
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Affiliation(s)
- Soichi Matsuo
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tsukasa Nabekura
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kenshiro Matsuda
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, Japan
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14
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Chu X, Tian W, Wang Z, Zhang J, Zhou R. Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials. Mol Cancer 2023; 22:93. [PMID: 37291608 DOI: 10.1186/s12943-023-01800-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/02/2023] [Indexed: 06/10/2023] Open
Abstract
Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Jing Zhang
- Department of Oncology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P.R. China.
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15
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Cifaldi L, Melaiu O, Giovannoni R, Benvenuto M, Focaccetti C, Nardozi D, Barillari G, Bei R. DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy. Front Immunol 2023; 14:1197053. [PMID: 37359555 PMCID: PMC10285446 DOI: 10.3389/fimmu.2023.1197053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
DNAM-1 is a major NK cell activating receptor and, together with NKG2D and NCRs, by binding specific ligands, strongly contributes to mediating the killing of tumor or virus-infected cells. DNAM-1 specifically recognizes PVR and Nectin-2 ligands that are expressed on some virus-infected cells and on a broad spectrum of tumor cells of both hematological and solid malignancies. So far, while NK cells engineered for different antigen chimeric receptors (CARs) or chimeric NKG2D receptor have been extensively tested in preclinical and clinical studies, the use of DNAM-1 chimeric receptor-engineered NK cells has been proposed only in our recent proof-of-concept study and deserves further development. The aim of this perspective study is to describe the rationale for using this novel tool as a new anti-cancer immunotherapy.
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Affiliation(s)
- Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | | | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
- Departmental Faculty of Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Daniela Nardozi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
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16
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Zhao J, Li L, Yin H, Feng X, Lu Q. TIGIT: An emerging immune checkpoint target for immunotherapy in autoimmune disease and cancer. Int Immunopharmacol 2023; 120:110358. [PMID: 37262959 DOI: 10.1016/j.intimp.2023.110358] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/11/2023] [Accepted: 05/15/2023] [Indexed: 06/03/2023]
Abstract
Immune checkpoints (ICs), also referred to as co-inhibitory receptors (IRs), are essential for regulating immune cell function to maintain tolerance and prevent autoimmunity. IRs, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have been shown to possess immunoregulatory properties that are relevant to various autoimmune diseases and cancers. Tumors are characterized by suppressive microenvironments with elevated levels of IRs on tumor-infiltrating lymphocytes (TILs). Therefore, IR blockade has shown great potential in cancer therapy and has even been approved for clinical use. However, other IRs, including cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), may also represent promising targets for anti-tumor therapy. The increasing importance of IRs in autoimmune diseases has become apparent. In mouse models, TIGIT pathway blockade or TIGIT deficiency has been linked to T cell overactivation and proliferation, exacerbation of inflammation, and increased susceptibility to autoimmune disorders. On the other hand, TIGIT activation has been shown to alleviate autoimmune disorders in murine models. Given these findings, we examine the effects of TIGIT and its potential as a therapeutic target for both autoimmune diseases and cancers. It is clear that TIGIT represents an emerging and exciting target for immunotherapy in these contexts.
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Affiliation(s)
- Junpeng Zhao
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Liming Li
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Huiqi Yin
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Xiwei Feng
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Qianjin Lu
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
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17
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Wang T, Qiao W, Xie Y, Ma J, Hu W, Yang L, Li X, Duan C, Wu S, Wang Y, Cheng K, Zhang Y, Zhuang R. CD226 deficiency exacerbated intestinal immune dysregulation in mice with dinitrochlorobenzene-induced atopic dermatitis. Immunology 2023. [PMID: 36938934 DOI: 10.1111/imm.13640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/16/2023] [Indexed: 03/21/2023] Open
Abstract
Intestinal mucosal immunity plays a pivotal role in host defence. In this study, we found that cluster of differentiation 226 (CD226) gene knockout (KO) led to more severe atopic dermatitis (AD)-related skin pathologies and bowel abnormalities in a 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model. Following DNCB administration, the expression of CD226 was elevated in intestinal mucosal tissues, including group 3 innate lymphoid cells (ILC3s) and CD4+ T cells of Peyer's patches (PPs). CD226 deficiency led to an overactive intestinal immune response in the AD-like mice, as evidenced by increased inflammation and Th1/Th2-related cytokine levels as well as increased Paneth cell numbers and antimicrobial peptide (AMP) expression, which was likely due to the higher interleukin (IL)-22 production in the lamina propria. Additionally, CD226 deficiency increased the production of IL-4 and IL-17 in mesenteric lymph nodes as well as the number of PPs and expression of immunoglobulin (Ig) A in B cells. Moreover, insufficient expression of CD226 affected the characterization of intraepithelial and lamina propria lymphocytes in the intestinal mucosa. Finally, the number of PPs was increased in CD4+ T cell-specific CD226 KO and regulatory T (Treg) cell-specific CD226 KO mice; thus, loss of CD226 in Treg cells resulted in impaired Treg cell-suppressive function. Therefore, our findings indicate that CD226 deficiency alters intestinal immune functionality in inflammatory diseases.
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Affiliation(s)
- Tingting Wang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wei Qiao
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yang Xie
- Department of Otolaryngological, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jingchang Ma
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wei Hu
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lu Yang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xuemei Li
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chujun Duan
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shuwen Wu
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yuling Wang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kun Cheng
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuan Zhang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ran Zhuang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
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18
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Jantz-Naeem N, Böttcher-Loschinski R, Borucki K, Mitchell-Flack M, Böttcher M, Schraven B, Mougiakakos D, Kahlfuss S. TIGIT signaling and its influence on T cell metabolism and immune cell function in the tumor microenvironment. Front Oncol 2023; 13:1060112. [PMID: 36874131 PMCID: PMC9982004 DOI: 10.3389/fonc.2023.1060112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 01/11/2023] [Indexed: 02/19/2023] Open
Abstract
One of the key challenges for successful cancer therapy is the capacity of tumors to evade immune surveillance. Tumor immune evasion can be accomplished through the induction of T cell exhaustion via the activation of various immune checkpoint molecules. The most prominent examples of immune checkpoints are PD-1 and CTLA-4. Meanwhile, several other immune checkpoint molecules have since been identified. One of these is the T cell immunoglobulin and ITIM domain (TIGIT), which was first described in 2009. Interestingly, many studies have established a synergistic reciprocity between TIGIT and PD-1. TIGIT has also been described to interfere with the energy metabolism of T cells and thereby affect adaptive anti-tumor immunity. In this context, recent studies have reported a link between TIGIT and the hypoxia-inducible factor 1-α (HIF1-α), a master transcription factor sensing hypoxia in several tissues including tumors that among others regulates the expression of metabolically relevant genes. Furthermore, distinct cancer types were shown to inhibit glucose uptake and effector function by inducing TIGIT expression in CD8+ T cells, resulting in an impaired anti-tumor immunity. In addition, TIGIT was associated with adenosine receptor signaling in T cells and the kynurenine pathway in tumor cells, both altering the tumor microenvironment and T cell-mediated immunity against tumors. Here, we review the most recent literature on the reciprocal interaction of TIGIT and T cell metabolism and specifically how TIGIT affects anti-tumor immunity. We believe understanding this interaction may pave the way for improved immunotherapy to treat cancer.
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Affiliation(s)
- Nouria Jantz-Naeem
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Romy Böttcher-Loschinski
- Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Katrin Borucki
- Institute of Clinical Chemistry, Department of Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Marisa Mitchell-Flack
- Department of Oncology, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Martin Böttcher
- Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Burkhart Schraven
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Dimitrios Mougiakakos
- Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Sascha Kahlfuss
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
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19
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Mace EM. Human natural killer cells: Form, function, and development. J Allergy Clin Immunol 2023; 151:371-385. [PMID: 36195172 PMCID: PMC9905317 DOI: 10.1016/j.jaci.2022.09.022] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 02/07/2023]
Abstract
Human natural killer (NK) cells are innate lymphoid cells that mediate important effector functions in the control of viral infection and malignancy. Their ability to distinguish "self" from "nonself" and lyse virally infected and tumorigenic cells through germline-encoded receptors makes them important players in maintaining human health and a powerful tool for immunotherapeutic applications and fighting disease. This review introduces our current understanding of NK cell biology, including key facets of NK cell differentiation and the acquisition and execution of NK cell effector function. Further, it addresses the clinical relevance of NK cells in both primary immunodeficiency and immunotherapy. It is intended to provide an up-to-date and comprehensive overview of this important and interesting innate immune effector cell subset.
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Affiliation(s)
- Emily M Mace
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York.
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20
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Milito ND, Zingoni A, Stabile H, Soriani A, Capuano C, Cippitelli M, Gismondi A, Santoni A, Paolini R, Molfetta R. NKG2D engagement on human NK cells leads to DNAM-1 hypo-responsiveness through different converging mechanisms. Eur J Immunol 2023; 53:e2250198. [PMID: 36440686 DOI: 10.1002/eji.202250198] [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: 09/30/2022] [Revised: 11/09/2022] [Accepted: 11/22/2022] [Indexed: 11/30/2022]
Abstract
Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM-1 play a pivotal role in anticancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently downmodulated and rendered functionally inactive. Of note, NKG2D internalization has been associated with the acquisition of a dysfunctional phenotype characterized by the cross-tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy, we demonstrate that NKG2D engagement on human NK cells impairs DNAM-1-mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppresses DNAM-1-mediated cytotoxic function, and by direct inhibition of DNAM-1-promoted signaling. Our results highlight a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may facilitate neoplastic cell evasion from NK cell-mediated clearance.
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Affiliation(s)
- Nadia D Milito
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Zingoni
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Helena Stabile
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Soriani
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristina Capuano
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Marco Cippitelli
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Angela Gismondi
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Angela Santoni
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.,IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - Rossella Paolini
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Rosa Molfetta
- Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
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21
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Anang V, Singh A, Kottarath SK, Verma C. Receptors of immune cells mediates recognition for tumors. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 194:219-267. [PMID: 36631194 DOI: 10.1016/bs.pmbts.2022.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Over the last few decades, the immune system has been steered toward eradication of cancer cells with the help of cancer immunotherapy. T cells, B cells, monocytes/macrophages, dendritic cells, T-reg cells, and natural killer (NK) cells are some of the numerous immune cell types that play a significant part in cancer cell detection and reduction of inflammation, and the antitumor response. Briefly stated, chimeric antigen receptors, adoptive transfer and immune checkpoint modulators are currently the subjects of research focus for successful immunotherapy-based treatments for a variety of cancers. This chapter discusses ongoing investigations on the mechanisms and recent developments by which receptors of immune cells especially that of lymphocytes and monocytes/macrophages regulate the detection of immune system leading to malignancies. We will also be looking into the treatment strategies based on these mechanisms.
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Affiliation(s)
- Vandana Anang
- International Center for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | | | - Sarat Kumar Kottarath
- Department of Experimental Therapeutics, MD Anderson Cancer Center, Huston, TX, United States.
| | - Chaitenya Verma
- Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, United States.
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22
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Murata R, Kinoshita S, Matsuda K, Kawaguchi A, Shibuya A, Shibuya K. G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4 + T Cell Activation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2304-2312. [PMID: 36323412 DOI: 10.4049/jimmunol.2200608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/12/2022] [Indexed: 02/17/2024]
Abstract
Although rs763361, which causes a nonsynonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAX accessory molecule-1 (DNAM-1) immunoreceptor, is a single-nucleotide polymorphism associated with autoimmune disease susceptibility, little is known about how the single-nucleotide polymorphism is involved in pathogenesis. In this study, we established human CD4+ T cell transfectants stably expressing wild-type (WT) or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater proinflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented p-Tyr322 of DNAM-1. We also established a mouse myelin Ag-specific CD4+ T cell transfectant stably expressing the chimeric DNAM-1 (chDNAM-1) consisting of the extracellular, transmembrane, and a part of intracellular regions of mouse DNAM-1 (residues 1-285) fused with the part of the intracellular region (residues 286-336) of human WT or G307S chDNAM-1. Adoptive transfer of the mouse T cell transfectant expressing the G307S chDNAM-1 into mice exacerbated experimental autoimmune encephalomyelitis compared with the transfer of cells expressing the WT chDNAM-1. These findings suggest that rs763361 is a gain-of-function mutation that enhances DNAM-1-mediated costimulatory signaling for proinflammatory responses.
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Affiliation(s)
- Rikito Murata
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- PhD Program in Human Biology, University of Tsukuba, Tsukuba, Japan
| | - Shota Kinoshita
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- PhD Program in Human Biology, University of Tsukuba, Tsukuba, Japan
| | - Kenshiro Matsuda
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
| | - Atsushi Kawaguchi
- Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; and
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
- R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
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23
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Persyn E, Wahlen S, Kiekens L, Van Loocke W, Siwe H, Van Ammel E, De Vos Z, Van Nieuwerburgh F, Matthys P, Taghon T, Vandekerckhove B, Van Vlierberghe P, Leclercq G. IRF2 is required for development and functional maturation of human NK cells. Front Immunol 2022; 13:1038821. [PMID: 36544762 PMCID: PMC9762550 DOI: 10.3389/fimmu.2022.1038821] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes that play an important role in the first line of defense against malignant or virus-infected cells. A better understanding of the transcriptional regulation of human NK cell differentiation is crucial to improve the efficacy of NK cell-mediated immunotherapy for cancer treatment. Here, we studied the role of the transcription factor interferon regulatory factor (IRF) 2 in human NK cell differentiation by stable knockdown or overexpression in cord blood hematopoietic stem cells and investigated its effect on development and function of the NK cell progeny. IRF2 overexpression had limited effects in these processes, indicating that endogenous IRF2 expression levels are sufficient. However, IRF2 knockdown greatly reduced the cell numbers of all early differentiation stages, resulting in decimated NK cell numbers. This was not caused by increased apoptosis, but by decreased proliferation. Expression of IRF2 is also required for functional maturation of NK cells, as the remaining NK cells after silencing of IRF2 had a less mature phenotype and showed decreased cytotoxic potential, as well as a greatly reduced cytokine secretion. Thus, IRF2 plays an important role during development and functional maturation of human NK cells.
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Affiliation(s)
- Eva Persyn
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Sigrid Wahlen
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Laura Kiekens
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Wouter Van Loocke
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Hannah Siwe
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Els Van Ammel
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Zenzi De Vos
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | - Patrick Matthys
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, K.U. Leuven, Leuven, Belgium
| | - Tom Taghon
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Bart Vandekerckhove
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Pieter Van Vlierberghe
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Georges Leclercq
- Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,Cancer Research Institute Ghent (CRIG), Ghent, Belgium,*Correspondence: Georges Leclercq,
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24
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Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints. Cancers (Basel) 2022; 14:cancers14225633. [PMID: 36428727 PMCID: PMC9688455 DOI: 10.3390/cancers14225633] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/04/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs.
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25
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Focaccetti C, Benvenuto M, Pighi C, Vitelli A, Napolitano F, Cotugno N, Fruci D, Palma P, Rossi P, Bei R, Cifaldi L. DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study. Front Immunol 2022; 13:886319. [PMID: 35967339 PMCID: PMC9367496 DOI: 10.3389/fimmu.2022.886319] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022] Open
Abstract
Adoptive transfer of engineered NK cells, one of clinical approaches to fight cancer, is gaining great interest in the last decade. However, the development of new strategies is needed to improve clinical efficacy and safety of NK cell-based immunotherapy. NK cell-mediated recognition and lysis of tumor cells are strictly dependent on the expression of ligands for NK cell-activating receptors NKG2D and DNAM-1 on tumor cells. Of note, the PVR/CD155 and Nectin-2/CD112 ligands for DNAM-1 are expressed primarily on solid tumor cells and poorly expressed in normal tissue cells. Here, we generated human NK cells expressing either the full length DNAM-1 receptor or three different DNAM-1-based chimeric receptor that provide the expression of DNAM-1 fused to a costimulatory molecule such as 2B4 and CD3ζ chain. Upon transfection into primary human NK cells isolated from healthy donors, we evaluated the surface expression of DNAM-1 and, as a functional readout, we assessed the extent of degranulation, cytotoxicity and the production of IFNγ and TNFα in response to human leukemic K562 cell line. In addition, we explored the effect of Nutlin-3a, a MDM2-targeting drug able of restoring p53 functions and known to have an immunomodulatory effect, on the degranulation of DNAM-1-engineered NK cells in response to human neuroblastoma (NB) LA-N-5 and SMS-KCNR cell lines. By comparing NK cells transfected with four different plasmid vectors and through blocking experiments, DNAM-1-CD3ζ-engineered NK cells showed the strongest response. Furthermore, both LA-N-5 and SMS-KCNR cells pretreated with Nutlin-3a were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector. Our results provide a proof-of-concept suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53.
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Affiliation(s)
- Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
| | - Chiara Pighi
- Research Unit of Clinical Immunology and Vaccinology, Dipartimento Pediatrico Universitario Ospedaliero (DPUO), Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | | | | | - Nicola Cotugno
- Research Unit of Clinical Immunology and Vaccinology, Dipartimento Pediatrico Universitario Ospedaliero (DPUO), Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Chair of Pediatrics, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Doriana Fruci
- Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Paolo Palma
- Research Unit of Clinical Immunology and Vaccinology, Dipartimento Pediatrico Universitario Ospedaliero (DPUO), Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Chair of Pediatrics, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Paolo Rossi
- Chair of Pediatrics, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
- Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
- Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- *Correspondence: Loredana Cifaldi,
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26
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Conner M, Hance KW, Yadavilli S, Smothers J, Waight JD. Emergence of the CD226 Axis in Cancer Immunotherapy. Front Immunol 2022; 13:914406. [PMID: 35812451 PMCID: PMC9263721 DOI: 10.3389/fimmu.2022.914406] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/26/2022] [Indexed: 01/31/2023] Open
Abstract
In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of manipulation in cancer. Central to this axis, CD226, TIGIT, and CD96 represent ligand (CD155)-competitive co-stimulatory/inhibitory receptors, analogous to the CTLA-4/B7/CD28 tripartite. The identification of PVRIG (CD112R) and CD112 has introduced complexity and enabled additional nodes of therapeutic intervention. By virtue of the clinical progression of TIGIT antagonists and emergence of novel CD96- and PVRIG-based approaches, our overall understanding of the 'CD226 axis' in cancer immunotherapy is starting to take shape. However, several questions remain regarding the unique characteristics of, and mechanistic interplay between, each receptor-ligand pair. This review provides an overview of the CD226 axis in the context of cancer, with a focus on the status of immunotherapeutic strategies (TIGIT, CD96, and PVRIG) and their underlying biology (i.e., cis/trans interactions). We also integrate our emerging knowledge of the immune populations involved, key considerations for Fc gamma (γ) receptor biology in therapeutic activity, and a snapshot of the rapidly evolving clinical landscape.
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27
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Chiang EY, Mellman I. TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy. J Immunother Cancer 2022; 10:jitc-2022-004711. [PMID: 35379739 PMCID: PMC8981293 DOI: 10.1136/jitc-2022-004711] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2022] [Indexed: 12/22/2022] Open
Abstract
Recent advances in understanding the roles of immune checkpoints in allowing tumors to circumvent the immune system have led to successful therapeutic strategies that have fundamentally changed oncology practice. Thus far, immunotherapies against only two checkpoint targets have been approved, CTLA-4 and PD-L1/PD-1. Antibody blockade of these targets enhances the function of antitumor T cells at least in part by relieving inhibition of the T cell costimulatory receptor CD28. These successes have stimulated considerable interest in identifying other pathways that may bte targeted alone or together with existing immunotherapies. One such immune checkpoint axis is comprised of members of the PVR/nectin family that includes the inhibitory receptor T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT). Interestingly, TIGIT acts to regulate the activity of a second costimulatory receptor CD226 that works in parallel to CD28. There are currently over two dozen TIGIT-directed blocking antibodies in various phases of clinical development, testament to the promise of modulating this pathway to enhance antitumor immune responses. In this review, we discuss the role of TIGIT as a checkpoint inhibitor, its interplay with the activating counter-receptor CD226, and its status as the next advance in cancer immunotherapy.
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Affiliation(s)
- Eugene Y Chiang
- Cancer Immunology, Genentech Inc, South San Francisco, California, USA
| | - Ira Mellman
- Cancer Immunology, Genentech Inc, South San Francisco, California, USA
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28
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Banta KL, Xu X, Chitre AS, Au-Yeung A, Takahashi C, O'Gorman WE, Wu TD, Mittman S, Cubas R, Comps-Agrar L, Fulzele A, Bennett EJ, Grogan JL, Hui E, Chiang EY, Mellman I. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8 + T cell responses. Immunity 2022; 55:512-526.e9. [PMID: 35263569 PMCID: PMC9287124 DOI: 10.1016/j.immuni.2022.02.005] [Citation(s) in RCA: 194] [Impact Index Per Article: 64.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 12/01/2021] [Accepted: 02/07/2022] [Indexed: 02/07/2023]
Abstract
Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT's ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.
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Affiliation(s)
- Karl L Banta
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Xiaozheng Xu
- Section of Cell & Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | | | - Amelia Au-Yeung
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | | | | | - Thomas D Wu
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | | | - Rafael Cubas
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | | | - Amit Fulzele
- Section of Cell & Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Eric J Bennett
- Section of Cell & Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Jane L Grogan
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Enfu Hui
- Section of Cell & Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Eugene Y Chiang
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
| | - Ira Mellman
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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29
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Zhou J, Zhang S, Guo C. Crosstalk between macrophages and natural killer cells in the tumor microenvironment. Int Immunopharmacol 2021; 101:108374. [PMID: 34824036 DOI: 10.1016/j.intimp.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/17/2022]
Abstract
The tumor microenvironment (TME) is jointly constructed by a variety of cell types, including tumor cells, immune cells, fibroblasts, and epithelial cells, among others. The cells within the TME interact with each other and with tumor cells to influence tumor development and progression. As the most abundant immune cells in the TME, macrophages regulate the immune network by not only secreting a large amount of versatile cytokines but also expressing a series of ligands or receptors on the surface to interact with other cells directly. Due to their strong plasticity, they exert both immunostimulatory and immunosuppressive effects in the complex TME. The major effector cells of the immune system that directly target cancer cells include but are not limited to natural killer cells (NKs), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T lymphocytes (CTLs). Among them, NK cells are the predominant innate lymphocyte subsets that mediate antitumor and antiviral responses. The activation and inhibition of NK cells are regulated by cytokines and the balance between activating and inhibitory receptors. There is an inextricable regulatory relationship between macrophages and NK cells. Herein, we systematically elaborate on the regulatory network between macrophages and NK cells through soluble mediator crosstalk and cell-to-cell interactions. We believe that a better understanding of the crosstalk between macrophages and NKs in the TME will benefit the development of novel macrophage- or NK cell-focused therapeutic strategies with superior efficacies in cancer therapy.
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Affiliation(s)
- Jingping Zhou
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Shaolong Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Changying Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
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30
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Shibuya A, Shibuya K. DNAM-1 versus TIGIT: competitive roles in tumor immunity and inflammatory responses. Int Immunol 2021; 33:687-692. [PMID: 34694361 DOI: 10.1093/intimm/dxab085] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
The co-stimulatory and co-inhibitory immunoreceptors DNAX accessory molecule-1 (DNAM-1) and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) are paired activating and inhibitory receptors on T cells and natural killer (NK) cells. They share the ligands poliovirus receptor (PVR, CD155) and its family member nectin-2 (CD112), which are highly expressed on antigen-presenting cells (APCs), tumors and virus-infected cells. Upon ligation with the ligands, DNAM-1 and TIGIT show reciprocal functions; whereas DNAM-1 promotes activation, proliferation, cytokine production and cytotoxic activity in effector lymphocytes, including CD4 + T-helper cells, CD8 + cytotoxic T lymphocytes and NK cells, TIGIT inhibits these DNAM-1 functions. On the other hand, DNAM-1 competes with TIGIT on regulatory T (Treg) cells in binding to CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function. Thus, whereas DNAM-1 enhances anti-tumor immunity and inflammatory responses by augmenting effector lymphocyte function and suppressing Treg cell function, TIGIT reciprocally suppresses these immune responses by suppressing effector lymphocyte function and augmenting Treg cell function. Thus, blockade of DNAM-1 and TIGIT function would be potential therapeutic approaches for patients with inflammatory diseases and those with cancers and virus infection, respectively.
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Affiliation(s)
- Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.,R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.,R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan
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31
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Fortes-Andrade T, Almeida JS, Sousa LM, Santos-Rosa M, Freitas-Tavares P, Casanova JM, Rodrigues-Santos P. The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy. Cancers (Basel) 2021; 13:cancers13153865. [PMID: 34359767 PMCID: PMC8345358 DOI: 10.3390/cancers13153865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present genetic differences, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for the respective treatments, which further decreases patient survival (<5 years). Natural Killer (NK) cells have a fundamental role in the control and immune surveillance of cancer development, progression and metastases. Notwithstanding the scarcity of studies to characterize NK cells in STS, it is noteworthy that the progression of these malignancies is associated with altered NK cells. These findings support the additional need to explore NK cell-based immunotherapy in STS; some clinical trials, although very tentatively, are already underway. Abstract Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for their respective treatments, which further decreases patient survival (<5 years). Despite some studies, little is known about the immunological profile of STS. As for the immunological profile of STS in relation to NK cells, there is also a shortage of studies. Observations made in solid tumors show that the infiltration of NK cells in tumors is associated with a good prognosis of the disease. Notwithstanding the scarcity of studies to characterize NK cells, their receptors, and ligands in STS, it is noteworthy that the progression of these malignancies is associated with altered NK phenotypes. Despite the scarcity of information on the function of NK cells, their phenotypes and their regulatory pathways in STS, the findings of this study support the additional need to explore NK cell-based immunotherapy in STS further. Some clinical trials, very tentatively, are already underway. STS clinical trials are still the basis for adoptive NK-cell and cytokine-based therapy.
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Affiliation(s)
- Tânia Fortes-Andrade
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
| | - Jani Sofia Almeida
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Luana Madalena Sousa
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
| | - Manuel Santos-Rosa
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Paulo Freitas-Tavares
- Coimbra Hospital and University Center (CHUC), Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, 3000-075 Coimbra, Portugal;
| | - José Manuel Casanova
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Hospital and University Center (CHUC), Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, 3000-075 Coimbra, Portugal;
| | - Paulo Rodrigues-Santos
- Center for Neuroscience and Cell Biology (CNC), Laboratory of Immunology and Oncology, University of Coimbra, 3004-504 Coimbra, Portugal; (T.F.-A.); (J.S.A.); (L.M.S.)
- Faculty of Medicine, Immunology Institute, University of Coimbra, 3004-504 Coimbra, Portugal;
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-85-77-77 (ext. 24-28-44)
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32
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Šunina M, Alnek K, Kisand K, Uibo R. Human CD4
+
and CD8
+
T lymphocyte subpopulations have significantly different surface expression patterns of CD226 and TIGIT molecules. Scand J Immunol 2021; 94:e13089. [DOI: 10.1111/sji.13089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/30/2021] [Accepted: 06/20/2021] [Indexed: 01/14/2023]
Affiliation(s)
- Marina Šunina
- Department of Immunology Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia
| | - Kristi Alnek
- Department of Immunology Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia
| | - Kai Kisand
- Department of Biomedicine Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia
| | - Raivo Uibo
- Department of Immunology Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia
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33
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Hansen K, Kumar S, Logronio K, Whelan S, Qurashi S, Cheng HY, Drake A, Tang M, Wall P, Bernados D, Leung L, Ophir E, Alteber Z, Cojocaru G, Galperin M, Frenkel M, White M, Hunter J, Liang SC, Kotturi MF. COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade. Cancer Immunol Immunother 2021; 70:3525-3540. [PMID: 33903974 DOI: 10.1007/s00262-021-02921-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 03/22/2021] [Indexed: 12/25/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.
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Affiliation(s)
- Kyle Hansen
- Compugen USA, Inc, South San Francisco, CA, USA
| | | | | | | | | | | | | | | | | | | | - Ling Leung
- Compugen USA, Inc, South San Francisco, CA, USA
| | - Eran Ophir
- Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel.
| | - Zoya Alteber
- Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel
| | - Gady Cojocaru
- Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel
| | - Moran Galperin
- Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel
| | - Masha Frenkel
- Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel
| | - Mark White
- Compugen USA, Inc, South San Francisco, CA, USA
| | - John Hunter
- Compugen USA, Inc, South San Francisco, CA, USA
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34
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Braun M, Aguilera AR, Sundarrajan A, Corvino D, Stannard K, Krumeich S, Das I, Lima LG, Meza Guzman LG, Li K, Li R, Salim N, Jorge MV, Ham S, Kelly G, Vari F, Lepletier A, Raghavendra A, Pearson S, Madore J, Jacquelin S, Effern M, Quine B, Koufariotis LT, Casey M, Nakamura K, Seo EY, Hölzel M, Geyer M, Kristiansen G, Taheri T, Ahern E, Hughes BGM, Wilmott JS, Long GV, Scolyer RA, Batstone MD, Landsberg J, Dietrich D, Pop OT, Flatz L, Dougall WC, Veillette A, Nicholson SE, Möller A, Johnston RJ, Martinet L, Smyth MJ, Bald T. CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 + T Cells. Immunity 2021; 53:805-823.e15. [PMID: 33053330 DOI: 10.1016/j.immuni.2020.09.010] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 05/21/2020] [Accepted: 09/15/2020] [Indexed: 12/20/2022]
Abstract
The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
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Affiliation(s)
- Matthias Braun
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Amelia Roman Aguilera
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ashmitha Sundarrajan
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Dillon Corvino
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Kimberley Stannard
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Sophie Krumeich
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Indrajit Das
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Luize G Lima
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Lizeth G Meza Guzman
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Kunlun Li
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Rui Li
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada
| | - Nazhifah Salim
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Maria Villancanas Jorge
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Sunyoung Ham
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Gabrielle Kelly
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Frank Vari
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ailin Lepletier
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ashwini Raghavendra
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Sally Pearson
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Jason Madore
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Sebastien Jacquelin
- Gordon and Jessie Gilmour Leukemia Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Maike Effern
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany; Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia
| | - Brodie Quine
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Lambros T Koufariotis
- Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Mika Casey
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Kyohei Nakamura
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Eun Y Seo
- Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA
| | - Michael Hölzel
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Matthias Geyer
- Institute of Structural Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Glen Kristiansen
- Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Touraj Taheri
- Pathology Queensland, Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia
| | - Elizabeth Ahern
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia
| | - Brett G M Hughes
- Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia
| | - James S Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Martin D Batstone
- Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia
| | - Jennifer Landsberg
- Department of Dermatology and Allergy, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Dimo Dietrich
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Oltin T Pop
- Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland; Department of Dermatology, Kantonsspital St.Gallen, St.Gallen, Switzerland
| | - William C Dougall
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - André Veillette
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada; Department of Medicine, University of Montréal, Montréal, QC, Canada
| | - Sandra E Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Andreas Möller
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Robert J Johnston
- Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA
| | - Ludovic Martinet
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse F-31000, France
| | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
| | - Tobias Bald
- Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
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Weulersse M, Asrir A, Pichler AC, Lemaitre L, Braun M, Carrié N, Joubert MV, Le Moine M, Do Souto L, Gaud G, Das I, Brauns E, Scarlata CM, Morandi E, Sundarrajan A, Cuisinier M, Buisson L, Maheo S, Kassem S, Agesta A, Pérès M, Verhoeyen E, Martinez A, Mazieres J, Dupré L, Gossye T, Pancaldi V, Guillerey C, Ayyoub M, Dejean AS, Saoudi A, Goriely S, Avet-Loiseau H, Bald T, Smyth MJ, Martinet L. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 + T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy. Immunity 2021; 53:824-839.e10. [PMID: 33053331 DOI: 10.1016/j.immuni.2020.09.006] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 05/15/2020] [Accepted: 09/10/2020] [Indexed: 01/16/2023]
Abstract
CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.
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Affiliation(s)
- Marianne Weulersse
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Assia Asrir
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Andrea C Pichler
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Lea Lemaitre
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Matthias Braun
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Nadège Carrié
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Marie-Véronique Joubert
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Marie Le Moine
- UCR-I (ULB Centre for Research in Immunology), Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, 6041 Belgium
| | - Laura Do Souto
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Guillaume Gaud
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France
| | - Indrajit Das
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Elisa Brauns
- UCR-I (ULB Centre for Research in Immunology), Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, 6041 Belgium
| | - Clara M Scarlata
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Elena Morandi
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France
| | | | - Marine Cuisinier
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Laure Buisson
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Sabrina Maheo
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Sahar Kassem
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Arantxa Agesta
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France
| | - Michaël Pérès
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Els Verhoeyen
- Université Côte d'Azur, INSERM, C3M, Nice, France; Centre international de recherche en infectiologie (CIRI), Inserm U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Alejandra Martinez
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Julien Mazieres
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Loïc Dupré
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Thomas Gossye
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France
| | - Vera Pancaldi
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Barcelona Supercomputing Center, Barcelona, Spain
| | - Camille Guillerey
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Maha Ayyoub
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Anne S Dejean
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France
| | - Abdelhadi Saoudi
- Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France
| | - Stanislas Goriely
- UCR-I (ULB Centre for Research in Immunology), Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, 6041 Belgium
| | - Hervé Avet-Loiseau
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France
| | - Tobias Bald
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Mark J Smyth
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Ludovic Martinet
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France; Institut Universitaire du Cancer, CHU Toulouse, France.
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Abstract
In this issue of Immunity, Weulersse et al. and Braun et al. explain how CD226 expression loss on CD8+ T cells impairs TCR-driven activation, and thereby anti-tumor effector responses, tantamount to taking the CD8+ T cell's foot off the gas pedal.
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Affiliation(s)
- Mary Philip
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
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Yamashita-Kanemaru Y, Oh-Oka K, Abe F, Shibuya K, Shibuya A. Suppression of Th1 and Th17 Proinflammatory Cytokines and Upregulation of FOXP3 Expression by a Humanized Anti-DNAM-1 Monoclonal Antibody. Monoclon Antib Immunodiagn Immunother 2021; 40:52-59. [PMID: 33900821 DOI: 10.1089/mab.2020.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
DNAM-1 is an activating immunoreceptor expressed on hematopoietic cells, including both CD4+ and CD8+ T cells, natural killer cells, and platelets. Since DNAM-1 is involved in the pathogenesis of various inflammatory diseases and cancers in humans as well as mouse models, it is a potential target for immunotherapy for these diseases. In this study, we generated a humanized neutralizing antihuman DNAM-1 monoclonal antibody (mAb), named TNAX101A, which contains an engineered Fc portion of human IgG1 to reduce Fc-mediated effector functions. We show that TNAX101A efficiently interfered the binding of DNAM-1 to its ligand CD155 and showed unique functions; it decreased production of the inflammatory cytokines such as interferon-gamma, tumor necrosis factor alpha, interleukin (IL)-6, IL-17A, and IL-17F by anti-CD3 antibody-stimulated or alloantigen-stimulated T cells and increased FOXP3 expression in anti-CD3-stimulated regulatory T (Treg) cells. These dual functions of TNAX101A may be advantageous for the treatment of T cell-mediated inflammatory diseases through both downregulation of effector T cell function and upregulation of Treg cell function.
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Affiliation(s)
- Yumi Yamashita-Kanemaru
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,TNAX Biopharma Corporation, Tsukuba, Japan
| | - Kyoko Oh-Oka
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Fumie Abe
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,TNAX Biopharma Corporation, Tsukuba, Japan
| | - Kazuko Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.,R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
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Alteber Z, Kotturi MF, Whelan S, Ganguly S, Weyl E, Pardoll DM, Hunter J, Ophir E. Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis. Cancer Discov 2021; 11:1040-1051. [PMID: 33687987 DOI: 10.1158/2159-8290.cd-20-1248] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/03/2020] [Accepted: 12/01/2020] [Indexed: 11/16/2022]
Abstract
Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. SIGNIFICANCE: Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti-PD-1/PD-L1 agents.
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Affiliation(s)
| | | | - Sarah Whelan
- Compugen USA, Inc., South San Francisco, California
| | - Sudipto Ganguly
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | | | - Drew M Pardoll
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | - John Hunter
- Compugen USA, Inc., South San Francisco, California
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TIGIT/CD226 Axis Regulates Anti-Tumor Immunity. Pharmaceuticals (Basel) 2021; 14:ph14030200. [PMID: 33670993 PMCID: PMC7997242 DOI: 10.3390/ph14030200] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indications, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells. This review discusses the recent discoveries regarding the roles of TIGIT and CD226 in immune cell function and their potential application in cancer immunotherapy.
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40
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Jin HS, Park Y. Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy. BMB Rep 2021. [PMID: 33298247 PMCID: PMC7851444 DOI: 10.5483/bmbrep.2021.54.1.229] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regu-lating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.
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Affiliation(s)
- Hyung-seung Jin
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yoon Park
- Theragnosis Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02456, Korea
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41
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Ding QQ, Chauvin JM, Zarour HM. Targeting novel inhibitory receptors in cancer immunotherapy. Semin Immunol 2020; 49:101436. [PMID: 33288379 DOI: 10.1016/j.smim.2020.101436] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022]
Abstract
T cells play a critical role in promoting tumor regression in both experimental models and humans. Yet, T cells that are chronically exposed to tumor antigen during cancer progression can become dysfunctional/exhausted and fail to induce tumor destruction. Such tumor-induced T cell dysfunction may occur via multiple mechanisms. In particular, immune checkpoint inhibitory receptors that are upregulated by tumor-infiltrating lymphocytes in many cancers limit T cell survival and function. Overcoming this inhibitory receptor-mediated T cell dysfunction has been a central focus of recent developments in cancer immunotherapy. Immunotherapies targeting inhibitory receptor pathways such as programmed cell death 1 (PD-1)/programmed death ligand 1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), alone or in combination, confer significant clinical benefits in multiple tumor types. However, many patients with cancer do not respond to immune checkpoint blockade, and dual PD-1/CTLA-4 blockade may cause serious adverse events, which limits its indications. Targeting novel non-redundant inhibitory receptor pathways contributing to tumor-induced T cell dysfunction in the tumor microenvironment may prove efficacious and non-toxic. This review presents preclinical and clinical findings supporting the roles of two key pathways-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domain (TIGIT)/CD226/CD96/CD112R-in cancer immunotherapy.
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Affiliation(s)
- Quan-Quan Ding
- Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
| | - Joe-Marc Chauvin
- Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
| | - Hassane M Zarour
- Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
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42
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Cantoni C, Wurzer H, Thomas C, Vitale M. Escape of tumor cells from the NK cell cytotoxic activity. J Leukoc Biol 2020; 108:1339-1360. [PMID: 32930468 DOI: 10.1002/jlb.2mr0820-652r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022] Open
Abstract
In recent years, NK cells, initially identified as potent cytotoxic effector cells, have revealed an unexpected complexity, both at phenotypic and functional levels. The discovery of different NK cell subsets, characterized by distinct gene expression and phenotypes, was combined with the characterization of the diverse functions NK cells can exert, not only as circulating cells, but also as cells localized or recruited in lymphoid organs and in multiple tissues. Besides the elimination of tumor and virus-infected cells, these functions include the production of cytokines and chemokines, the regulation of innate and adaptive immune cells, the influence on tissue homeostasis. In addition, NK cells display a remarkable functional plasticity, being able to adapt to the environment and to develop a kind of memory. Nevertheless, the powerful cytotoxic activity of NK cells remains one of their most relevant properties, particularly in the antitumor response. In this review, the process of tumor cell recognition and killing mediated by NK cells, starting from the generation of cytolytic granules and recognition of target cell, to the establishment of the NK cell immunological synapse, the release of cytotoxic molecules, and consequent tumor cell death is described. Next, the review focuses on the heterogeneous mechanisms, either intrinsic to tumors or induced by the tumor microenvironment, by which cancer cells can escape the NK cell-mediated attack.
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Affiliation(s)
- Claudia Cantoni
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.,Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Hannah Wurzer
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.,Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Clément Thomas
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Massimo Vitale
- UO Immunologia, IRCCS Ospedale Policlinico San Martino Genova, Genoa, Italy
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Abstract
Tumors evade immune-mediated recognition through multiple mechanisms of immune escape. On chronic tumor antigen exposure, T cells become dysfunctional/exhausted and upregulate various checkpoint inhibitory receptors (IRs) that limit T cells' survival and function. During the last decade, immunotherapies targeting IRs such as programmed cell death receptor 1 (PD-1) and anticytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have provided ample evidence of clinical benefits in many solid tumors. Beyond CTLA-4 and PD-1, multiple other IRs are also targeted with immune checkpoint blockade in the clinic. Specifically, T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a promising new target for cancer immunotherapy. TIGIT is upregulated by immune cells, including activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. There is now ample evidence that the TIGIT pathway regulates T cell-mediated and natural killer cell-mediated tumor recognition in vivo and in vitro. Dual PD-1/TIGIT blockade potently increases tumor antigen-specific CD8+ T cell expansion and function in vitro and promotes tumor rejection in mouse tumor models. These findings support development of ongoing clinical trials with dual PD-1/TIGIT blockade in patients with cancer.
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Affiliation(s)
- Joe-Marc Chauvin
- Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hassane M Zarour
- Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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44
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Huang Z, Qi G, Miller JS, Zheng SG. CD226: An Emerging Role in Immunologic Diseases. Front Cell Dev Biol 2020; 8:564. [PMID: 32850777 PMCID: PMC7396508 DOI: 10.3389/fcell.2020.00564] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 06/15/2020] [Indexed: 01/03/2023] Open
Abstract
CD226, a member of the immunoglobulin superfamily, is a functional protein initially expressed on natural killer and T cells. In recent years, the function of CD226 has been increasingly realized and researched. Accumulating evidence shows that CD226 is closely related to the occurrence of autoimmune diseases, infectious diseases, and tumors. Because of the CD226’s increasing importance, the author herein discusses the structure, mechanism of action, and role of CD226 in various pathophysiological environments, allowing for further understanding of the function of CD226 and providing the basis for further research in related diseases.
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Affiliation(s)
- Zhiyi Huang
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Guangyin Qi
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Joseph S Miller
- Ohio University Heritage College of Osteopathic Medicine, Dublin, OH, United States
| | - Song Guo Zheng
- Department of Internal Medicine, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, United States
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45
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Research Progress on NK Cell Receptors and Their Signaling Pathways. Mediators Inflamm 2020; 2020:6437057. [PMID: 32774149 PMCID: PMC7396059 DOI: 10.1155/2020/6437057] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/25/2020] [Accepted: 06/20/2020] [Indexed: 12/17/2022] Open
Abstract
Natural killer cells (NK cells) play an important role in innate immunity. NK cells recognize self and nonself depending on the balance of activating receptors and inhibitory receptors. After binding to their ligands, NK cell receptors trigger subsequent signaling conduction and then determine whether NK is activated or inhibited. Furthermore, NK cell response includes cytotoxicity and cytokine release, which is tightly related to the activation of NK cell-activating receptors and the inhibition of inhibitory receptors on the surfaces of NK cells. The expression and function of NK cell surface receptors also alter in virus infection, tumor, and autoimmune diseases and influence the occurrence and development of diseases. So, it is important to understand the mechanism of recognition between NK receptors and their ligands in pathological conditions and the signaling pathways of NK cell receptors. This review mainly summarizes the research progress on NK cell surface receptors and their signal pathways.
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46
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Human peripheral blood DNAM-1 neg NK cells are a terminally differentiated subset with limited effector functions. Blood Adv 2020; 3:1681-1694. [PMID: 31167820 DOI: 10.1182/bloodadvances.2018030676] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 04/25/2019] [Indexed: 01/03/2023] Open
Abstract
Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56dim NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56bright and CD56dimDNAM-1pos NK cell subsets, CD56dimDNAM-1neg NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56dimDNAM-1neg NK cells impaired CD56dimDNAM-1pos NK cell-mediated killing, indicating a potential inhibitory role for the CD56dimDNAM-1neg NK cell subset. Transcriptome analysis revealed that CD56dimDNAM-1neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56dimDNAM-1neg NK cells were found to differentiate from CD56dimDNAM-1pos NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56dimDNAM-1pos/CD56dimDNAM-1neg NK cell ratios and reduced cytotoxic activity of CD56dimDNAM-1pos NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell-targeting therapies.
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47
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Chauvin JM, Ka M, Pagliano O, Menna C, Ding Q, DeBlasio R, Sanders C, Hou J, Li XY, Ferrone S, Davar D, Kirkwood JM, Johnston RJ, Korman AJ, Smyth MJ, Zarour HM. IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma. Clin Cancer Res 2020; 26:5520-5533. [PMID: 32591463 DOI: 10.1158/1078-0432.ccr-20-0575] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/03/2020] [Accepted: 06/22/2020] [Indexed: 01/05/2023]
Abstract
PURPOSE Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell-mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell-mediated tumor reactivity. EXPERIMENTAL DESIGN We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell-mediated cytotoxicity in vitro and in two mouse models. RESULTS NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT- NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I-deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell-mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade. CONCLUSIONS Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8+ T-cell-mediated immunity.See related commentary by Pietra et al., p. 5274.
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Affiliation(s)
- Joe-Marc Chauvin
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Mignane Ka
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Ornella Pagliano
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Carmine Menna
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Quanquan Ding
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Richelle DeBlasio
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Cindy Sanders
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Jiajie Hou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xian-Yang Li
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Diwakar Davar
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - John M Kirkwood
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Robert J Johnston
- Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California
| | - Alan J Korman
- Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California
| | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Hassane M Zarour
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. .,Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
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48
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Lupo KB, Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol 2020; 13:76. [PMID: 32532329 PMCID: PMC7291472 DOI: 10.1186/s13045-020-00913-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 06/04/2020] [Indexed: 12/21/2022] Open
Abstract
Natural killer (NK) cells are powerful immune effectors, modulating their anti-tumor function through a balance activating and inhibitor ligands on their cell surface. Though still emerging, cancer immunotherapies utilizing NK cells are proving promising as a modality for the treatment of a number of solid tumors, including glioblastoma (GBM) and other gliomas, but are often limited due to complex immunosuppression associated with the GBM tumor microenvironment which includes overexpression of inhibitory receptors on GBM cells. CD155, or poliovirus receptor (PVR), has recently emerged as a pro-tumorigenic antigen, overexpressed on GBM and contributing to increased GBM migration and aggressiveness. CD155 has also been established as an immunomodulatory receptor, able to both activate NK cells through interactions with CD226 (DNAM-1) and CD96 and inhibit them through interaction with TIGIT. However, NK cell TIGIT expression has been shown to be upregulated in cancer, establishing CD155 as a predominantly inhibitory receptor within the context of GBM and other solid tumors, and rendering it of interest as a potential target for antigen-specific NK cell-based immunotherapy. This review will explore the function of CD155 within GBM as it relates to tumor migration and NK cell immunoregulation, as well as pre-clinical and clinical targeting of CD155/TIGIT and the potential that this pathway holds for the development of emerging NK cell-based immunotherapies.
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MESH Headings
- Animals
- Antigens, CD/immunology
- Antigens, CD/physiology
- Antigens, Differentiation, T-Lymphocyte/immunology
- Antigens, Differentiation, T-Lymphocyte/physiology
- Antineoplastic Agents, Immunological/therapeutic use
- Cell Adhesion
- Cell Movement
- Glioblastoma/immunology
- Glioblastoma/pathology
- Glioblastoma/therapy
- Humans
- Immunotherapy/methods
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Mice
- Neoplasm Invasiveness/immunology
- Neoplasm Invasiveness/prevention & control
- Neoplasm Metastasis
- Oncolytic Virotherapy
- Poliovirus/physiology
- Reassortant Viruses/physiology
- Receptors, Immunologic/immunology
- Receptors, Immunologic/physiology
- Receptors, Virus/antagonists & inhibitors
- Receptors, Virus/immunology
- Rhinovirus/physiology
- Tumor Microenvironment/immunology
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Affiliation(s)
- Kyle B Lupo
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA
| | - Sandro Matosevic
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA.
- Purdue Center for Cancer Research, West Lafayette, IN, 47906, USA.
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49
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Meza Guzman LG, Keating N, Nicholson SE. Natural Killer Cells: Tumor Surveillance and Signaling. Cancers (Basel) 2020; 12:cancers12040952. [PMID: 32290478 PMCID: PMC7226588 DOI: 10.3390/cancers12040952] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.
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Affiliation(s)
- Lizeth G. Meza Guzman
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence: (L.G.M.G.); (S.E.N.); Tel.: +61-9345-2555 (S.E.N.)
| | - Narelle Keating
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Sandra E. Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence: (L.G.M.G.); (S.E.N.); Tel.: +61-9345-2555 (S.E.N.)
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50
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Zamai L, Del Zotto G, Buccella F, Gabrielli S, Canonico B, Artico M, Ortolani C, Papa S. Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy. Cells 2020; 9:cells9030753. [PMID: 32204481 PMCID: PMC7140651 DOI: 10.3390/cells9030753] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/09/2020] [Accepted: 03/13/2020] [Indexed: 12/31/2022] Open
Abstract
The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.
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Affiliation(s)
- Loris Zamai
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
- INFN-Gran Sasso National Laboratory, Assergi, 67100 L’Aquila, Italy
- Correspondence: ; Tel.: +39-0722-304319; Fax: +39-0722-304319
| | - Genny Del Zotto
- Area Aggregazione Servizi e Laboratori Diagnostici, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Flavia Buccella
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
| | - Sara Gabrielli
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
| | - Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
| | - Marco Artico
- Department of Sensory Organs, Sapienza University of Rome, 00161 Rome, Italy
| | - Claudio Ortolani
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
| | - Stefano Papa
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
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