Review
. 2019 Sep; 2055:23-60.
doi: 10.1007/978-1-4939-9773-2_2.

Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors

Diwakar Davar 1 Hassane M Zarour 2 
Affiliations
  • PMID: 31502146
  •     172 References
  •     2 citations

Abstract

Tumor development is characterized by the accumulation of mutational and epigenetic changes that transform normal cells and survival pathways into self-sustaining cells capable of untrammeled growth. Although multiple modalities including surgery, radiation, and chemotherapy are available for the treatment of cancer, the benefits conferred are often limited. The immune system is capable of specific, durable, and adaptable responses. However, cancers hijack immune mechanisms such as negative regulatory checkpoints that have evolved to limit inflammatory and immune responses to thwart effective antitumor immunity. The development of monoclonal antibodies against inhibitory receptors expressed by immune cells has produced durable responses in a broad array of advanced malignancies and heralded a new dawn in the cancer armamentarium. However, these remarkable responses are limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Preclinical and clinical studies with immune checkpoint blockade are exploring the therapeutic potential antibody-based therapy targeting multiple inhibitory receptors. In this chapter, we discuss the current understanding of the structure, ligand specificities, function, and signaling activities of various inhibitory receptors. Additionally, we discuss the current development status of various immune checkpoint inhibitors targeting these negative immune receptors and highlight conceptual gaps in knowledge.

Keywords: BTLA; CTLA-4; Immunotherapy; Inhibitory receptors; LAG-3; PD-1; TIGIT; TIM-3; VISTA.

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Cancer Res, 2011 Nov 24; 72(2). PMID: 22108823    Free PMC article.
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J Immunol, 2008 Apr 22; 180(9). PMID: 18424711
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Erhu Cao, Xingxing Zang, +12 authors, Steven C Almo.
Immunity, 2007 Mar 17; 26(3). PMID: 17363302
Identification of CD112R as a novel checkpoint for human T cells.
Yuwen Zhu, Alessandro Paniccia, +6 authors, Barish H Edil.
J Exp Med, 2016 Jan 13; 213(2). PMID: 26755705    Free PMC article.
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Alexander C Huang, Michael A Postow, +31 authors, E John Wherry.
Nature, 2017 Apr 12; 545(7652). PMID: 28397821    Free PMC article.
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CTLA-4 and Autoimmunity: New Twists in the Tale.
Lucy S K Walker.
Trends Immunol, 2015 Nov 26; 36(12). PMID: 26596798    Free PMC article.
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Nat Immunol, 2012 Jul 31; 13(9). PMID: 22842346    Free PMC article.
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Immunity, 2010 Sep 28; 33(3). PMID: 20870175
BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection.
Marcos W Steinberg, Yujun Huang, +3 authors, Mitchell Kronenberg.
PLoS One, 2013 Nov 10; 8(10). PMID: 24205057    Free PMC article.
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J Immunol, 2010 Jan 20; 184(4). PMID: 20083673    Free PMC article.
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Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
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Immunogenetics, 1994 Jan 01; 39(3). PMID: 7506235
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
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Nature, 2016 Aug 09; 537(7620). PMID: 27501248    Free PMC article.
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Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
Caroline Robert, Luc Thomas, +21 authors, Jedd D Wolchok.
N Engl J Med, 2011 Jun 07; 364(26). PMID: 21639810
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SHP2 sails from physiology to pathology.
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Eur J Med Genet, 2015 Sep 06; 58(10). PMID: 26341048
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J Exp Med, 2012 May 30; 209(6). PMID: 22641383    Free PMC article.
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Nat Commun, 2016 Feb 18; 7. PMID: 26883990    Free PMC article.
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Drew M Pardoll.
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Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily.
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Cell, 1989 Mar 10; 56(5). PMID: 2538245
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CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.
Julien Fourcade, Zhaojun Sun, +7 authors, Hassane M Zarour.
Cancer Res, 2011 Dec 30; 72(4). PMID: 22205715    Free PMC article.
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Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues.
Hong Chen, Chrysoula I Liakou, +8 authors, Padmanee Sharma.
Proc Natl Acad Sci U S A, 2009 Feb 10; 106(8). PMID: 19202079    Free PMC article.
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J Immunol, 2011 Jan 05; 186(3). PMID: 21199897    Free PMC article.
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VISTA Regulates the Development of Protective Antitumor Immunity.
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PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.
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Proc Natl Acad Sci U S A, 2003 Apr 17; 100(9). PMID: 12697896    Free PMC article.
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PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs.
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Cell Rep, 2015 Sep 15; 12(12). PMID: 26365186
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
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Cancer Discov, 2015 Dec 10; 6(2). PMID: 26645196    Free PMC article.
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Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma.
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A molecular perspective of CTLA-4 function.
Wendy A Teft, Mark G Kirchhof, Joaquín Madrenas.
Annu Rev Immunol, 2006 Mar 23; 24. PMID: 16551244
Highly Cited. Review.
T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling.
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Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma.
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J Immunol, 2005 Oct 21; 175(9). PMID: 16237114
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Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.
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Nature, 2002 Feb 02; 415(6871). PMID: 11823861
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Reversing T-cell Dysfunction and Exhaustion in Cancer.
Hassane M Zarour.
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B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator.
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Nat Immunol, 2004 Nov 30; 6(1). PMID: 15568026
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The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.
Robert J Johnston, Laetitia Comps-Agrar, +9 authors, Jane L Grogan.
Cancer Cell, 2014 Dec 04; 26(6). PMID: 25465800
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Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.
Creg J Workman, Kari J Dugger, Dario A A Vignali.
J Immunol, 2002 Nov 08; 169(10). PMID: 12421911
TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression.
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PLoS One, 2012 Mar 01; 7(2). PMID: 22363469    Free PMC article.
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Nat Immunol, 2001 Feb 27; 2(3). PMID: 11224527
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Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
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J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    Free PMC article.
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J Immunol, 2006 Sep 20; 177(7). PMID: 16982872    Free PMC article.
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PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.
Loise M Francisco, Victor H Salinas, +4 authors, Arlene H Sharpe.
J Exp Med, 2009 Dec 17; 206(13). PMID: 20008522    Free PMC article.
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P S Linsley, J Bradshaw, +3 authors, R S Mittler.
Immunity, 1996 Jun 01; 4(6). PMID: 8673700
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BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties.
Cara L Haymaker, Richard C Wu, +8 authors, Laszlo G Radvanyi.
Oncoimmunology, 2015 Sep 26; 4(8). PMID: 26405566    Free PMC article.
The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms.
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Hum Pathol, 2010 Jul 27; 41(10). PMID: 20656318    Free PMC article.
CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
Chrysoula I Liakou, Ashish Kamat, +5 authors, Padmanee Sharma.
Proc Natl Acad Sci U S A, 2008 Sep 27; 105(39). PMID: 18818309    Free PMC article.
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Julien Fourcade, Pavol Kudela, +8 authors, Hassane M Zarour.
J Immunother, 2008 Sep 10; 31(8). PMID: 18779741    Free PMC article.
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Immunity, 1999 Nov 05; 11(4). PMID: 10549630
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K M Lee, E Chuang, +7 authors, J A Bluestone.
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Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
Stefani Spranger, Riyue Bao, Thomas F Gajewski.
Nature, 2015 May 15; 523(7559). PMID: 25970248
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Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex.
Deanne M Compaan, Lino C Gonzalez, +3 authors, Sarah G Hymowitz.
J Biol Chem, 2005 Sep 20; 280(47). PMID: 16169851
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
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Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
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Jianjun Gao, Lewis Zhichang Shi, +13 authors, Padmanee Sharma.
Cell, 2016 Sep 27; 167(2). PMID: 27667683    Free PMC article.
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Jesse M Zaretsky, Angel Garcia-Diaz, +26 authors, Antoni Ribas.
N Engl J Med, 2016 Jul 20; 375(9). PMID: 27433843    Free PMC article.
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Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
Manu Rangachari, Chen Zhu, +13 authors, Vijay K Kuchroo.
Nat Med, 2012 Aug 07; 18(9). PMID: 22863785    Free PMC article.
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Creg J Workman, Dario A A Vignali.
Eur J Immunol, 2003 Apr 03; 33(4). PMID: 12672063
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Creg J Workman, Dennis S Rice, +2 authors, Dario A A Vignali.
Eur J Immunol, 2002 Sep 05; 32(8). PMID: 12209638
BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints.
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Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells.
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Eur J Immunol, 2005 Jun 23; 35(7). PMID: 15971272
A crucial role for HVEM and BTLA in preventing intestinal inflammation.
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Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.
R Brad Jones, Lishomwa C Ndhlovu, +24 authors, Mario A Ostrowski.
J Exp Med, 2008 Nov 13; 205(12). PMID: 19001139    Free PMC article.
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Time to dissect the autoimmune etiology of cancer antibody immunotherapy.
Michael Dougan, Massimo Pietropaolo.
J Clin Invest, 2020 Jan 03; 130(1). PMID: 31895048    Free PMC article.
Review.
Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders.
Nicholas A Maskalenko, Dmitry Zhigarev, Kerry S Campbell.
Nat Rev Drug Discov, 2022 Mar 23;. PMID: 35314852
Review.