. 2020 Mar; 20(1):e3.
doi: 10.4110/in.2020.20.e3.

Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy

Seongju Jeong 1 Su-Hyung Park 1 
  • PMID: 32158591
  •     135 References
  •     17 citations


Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.

Keywords: Cancer, Immunotherapy; Costimulatory T-cell receptors; T-Lymphocytes.

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Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice.
Li-Zhen He, Naseem Prostak, +9 authors, Tibor Keler.
J Immunol, 2013 Sep 13; 191(8). PMID: 24026078
Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.
Adam D Cohen, David A Schaer, +10 authors, Jedd D Wolchok.
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Hum Immunol, 2006 May 16; 67(1-2). PMID: 16698419
Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities.
Matthias Wolfl, Jürgen Kuball, +4 authors, Philip D Greenberg.
Blood, 2007 Mar 21; 110(1). PMID: 17371945    Free PMC article.
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Takashi Tsukishiro, Albert D Donnenberg, Theresa L Whiteside.
Cancer Immunol Immunother, 2003 Jun 27; 52(10). PMID: 12827303
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Curr Opin Immunol, 2012 Jan 31; 24(2). PMID: 22285893
Immunosurveillance and therapy of multiple myeloma are CD226 dependent.
Camille Guillerey, Lucas Ferrari de Andrade, +12 authors, Ludovic Martinet.
J Clin Invest, 2015 Apr 22; 125(5). PMID: 25893601    Free PMC article.
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Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma.
Weiyi Peng, Leila J Williams, +17 authors, Patrick Hwu.
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OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
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DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors.
Susan Gilfillan, Christopher J Chan, +6 authors, Marco Colonna.
J Exp Med, 2008 Nov 26; 205(13). PMID: 19029380    Free PMC article.
Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343.
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Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
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ICOS signal facilitates Foxp3 transcription to favor suppressive function of regulatory T cells.
Qianmei Chen, Lijun Mo, +5 authors, Zhiming Hu.
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A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
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The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.
Anne Månsson Kvarnhammar, Niina Veitonmäki, +16 authors, Peter Ellmark.
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OX40 ligand shuts down IL-10-producing regulatory T cells.
Tomoki Ito, Yui-Hsi Wang, +5 authors, Yong-Jun Liu.
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Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy.
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Julian A Marin-Acevedo, Aixa E Soyano, +2 authors, Yanyan Lou.
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Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells.
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Gene Ther, 2011 Dec 02; 19(11). PMID: 22130449
CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth.
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Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.
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Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth.
J Kjaergaard, J Tanaka, +3 authors, S Shu.
Cancer Res, 2000 Oct 18; 60(19). PMID: 11034096
CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor.
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Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection.
Alison Crawford, Jill M Angelosanto, +4 authors, E John Wherry.
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Coalition Forces of Immunologists and Oncologists for Defeating Cancer.
Eui-Cheol Shin.
Immune Netw, 2020 Mar 12; 20(1). PMID: 32158589    Free PMC article.
B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes.
Gihoon You, Yangsoon Lee, +18 authors, Seung-Woo Lee.
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The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity.
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Inflammation and tumor progression: signaling pathways and targeted intervention.
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Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies.
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Tumor-Infiltrating Neutrophils and Non-Classical Monocytes May Be Potential Therapeutic Targets for HER2negative Gastric Cancer.
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Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways.
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Neoantigen-reactive T cell: An emerging role in adoptive cellular immunotherapy.
Yicheng Zhu, Youkun Qian, +2 authors, Bin Li.
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Expression Dynamics of the O-Glycosylated Proteins Recognized by Amaranthus leucocarpus Lectin in T Lymphocytes and Its Relationship With Moesin as an Alternative Mechanism of Cell Activation.
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Induction of Peptide-specific CTL Activity and Inhibition of Tumor Growth Following Immunization with Nanoparticles Coated with Tumor Peptide-MHC-I Complexes.
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Immune Checkpoint Gene Expression Profiling Identifies Programmed Cell Death Ligand-1 Centered Immunologic Subtypes of Oral and Squamous Cell Carcinoma With Favorable Survival.
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Targeted Immunotherapy for Autoimmune Disease.
Seung Min Jung, Wan-Uk Kim.
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Commensal Microbiota and Cancer Immunotherapy: Harnessing Commensal Bacteria for Cancer Therapy.
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CAR T Cell Immunotherapy Beyond Haematological Malignancy.
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Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy.
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Engineering strategies to enhance oncolytic viruses in cancer immunotherapy.
Yaomei Tian, Daoyuan Xie, Li Yang.
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