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Evaluating the Potential for B7-H4 As an Immunoregulatory Target

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Evaluating the Potential for B7-H4 As an Immunoregulatory Target Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target 3 Heather L. MacGregor1,2 and Pamela S. Ohashi1-3* 4 5 6 7 1Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, 8 Toronto, Ontario, Canada 9 2Department of Immunology, University of Toronto, Toronto, Ontario, Canada 10 3Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 11 12 13 Running Title: Evaluating B7-H4 as a Potential Immunoregulatory Target 14 Keywords: B7-H4; immunosuppression; co-inhibitory molecule; immunotherapy; tumor 15 microenvironment 16 17 Funding sources: This work was supported by grants from the Canadian Institute for Health 18 Research awarded to P.S. Ohashi. 19 20 *Corresponding Author: Pamela S. Ohashi, Princess Margaret Cancer Centre, 610 University 21 Avenue, Suite 8-407, Toronto, Ontario M5G 2M9, Canada. Phone: 416-946-2357; Fax: 416-204- 22 2276; e-mail: [email protected] 23 Disclosures: The authors have no financial conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 (Abstract: 152 words; Body: 2937 words; 2 figures, 1 table) 25 Abstract: With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, 26 there is tremendous interest in finding new ways to augment anti-tumor responses by targeting 27 other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of 28 the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine 29 production through ligation of an unknown receptor expressed by activated T cells. Notably, B7- 30 H4 protein expression is observed in a high proportion of patients’ tumors across a wide variety 31 of malignancies. This high expression by tumors in combination with its low or absent protein 32 expression in normal tissues makes B7-H4 an attractive immunotherapeutic target. Preclinical 33 investigation into B7-H4-specific CAR T cells, antibody-mediated blockade of B7-H4, and anti- 34 B7-H4 drug conjugates have shown anti-tumor efficacy in mouse models. The first clinical trials 35 have been completed to assess the safety and efficacy of a B7-H4 fusion protein in ameliorating 36 rheumatoid arthritis. 37 38 39 40 41 42 43 44 45 46 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 47 Background 48 The B7 family of immune-regulatory proteins is composed of ten members, B7-1 (CD80), 49 B7-2 (CD86), PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H2 (ICOSL), B7-H3 (CD276), B7-H4, B7- 50 H5 (VISTA), B7-H6, and B7-H7 (HHLA2), all of which are membrane-anchored proteins with 51 extracellular immunoglobulin-like domains important in the binding of their ligands (1). 52 Members of this family can be expressed on various cell types, such as antigen presenting cells 53 (APCs), T cells, and tumor cells (Figure 1). B7-H4 (B7x, B7S1, DD-0110, Vtcn1) was first 54 identified in 2003 through sequence similarities with other B7 family members (2–4). It is 55 heavily glycosylated, glycosylphosphatidylinositol (GPI)-linked (3,4), and plays an inhibitory 56 role in T cell function by limiting T cell proliferation, cytokine production and cytotoxicity (2– 57 4). 58 B7-H4 shows a high degree of conservation of core amino acid residues with other B7 59 family members, but the residues involved in ligand-binding for B7-1 (CD80) or B7-2 (CD86) 60 are not conserved (3). Experiments have shown that B7-H4 does not share binding partners with 61 other B7 family members as no interaction has been observed between B7-H4 and CD28 (2,4), 62 CTLA-4(3,4), ICOS, or PD-1 (2–4). Although BTLA was proposed to be the binding partner of 63 B7-H4 (5), subsequent experiments were unable to demonstrate the binding of a B7-H4-Fc 64 fusion protein to cells stably expressing BTLA (6). As yet, the B7-H4 receptor has not been 65 identified. 66 67 Expression and function of B7-H4 68 B7-H4 transcripts have been detected in a wide variety of tissues (2,7,8), while B7-H4 69 protein expression is tightly regulated and shows limited expression in most normal tissues 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 70 (3,7,9–14). However, it has been observed in certain tissues including thymus, spleen (3), 71 kidney, placenta (9,10), female genital tract, lung, and pancreas (10). 72 Alterations in B7-H4 expression in various in vivo models demonstrate its 73 immunosuppressive role. Transgenic over-expression of B7-H4 in pancreatic islets did not 74 prevent islet inflammation (8) but protected mice from developing diabetes in the presence of T 75 cells expressing islet-specific transgenic T cell receptors (TCRs) BDC2.5 (8) or AI4αβ (15). On 76 the non-obese diabetic (NOD) background, a mouse strain prone to developing diabetes, the loss 77 of B7-H4 expression on islet cells coincides with diabetes progression, and treatment that 78 inhibits B7-H4 loss delays diabetes onset (16). Loss of B7-H4 in these models accelerated 79 diabetes onset and severity (8,15,16). Detection of B7-H4 in human pancreatic tissue (10) and in 80 the sera of type 1 diabetes patients suggest it may also have an important role in the progression 81 of human disease (17). 82 Other in vivo models also support an immunosuppressive role for B7-H4. 83 Overexpression of B7-H4 in transplanted islets prolonged transplant survival and reduced pro- 84 inflammatory infiltrates (18), and delivery of a B7-H4-Ig fusion protein protected mice against 85 concanavalin A-induced hepatic injury (19). Additionally, host deficiency in B7-H4 conferred 86 resistance to a lethal pulmonary infection with S. pneumonia (20). In this model, disease 87 amelioration occurred in conjunction with an increase in infiltrating CD4 helper and CD8 88 cytotoxic T cells, and a concurrent decrease in neutrophils (20). Collectively, these findings 89 indicate that B7-H4 plays an immunosuppressive and tissue-protective role in multiple mouse 90 models. 91 92 B7-H4 in immunity 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 93 Controversy exists as to which immune populations express B7-H4. In mice, Prasad et al. 94 (2003) observed B7-H4 on a minor population of T cells, the majority of B cells (defined as 95 B220+), and thioglycolate-stimulated macrophages (2); and while Sica et al. (2003) did not 96 observe B7-H4 on resting human T cells, B cells, or monocytes, its expression could be induced 97 by phytohaemagglutinin (PHA), lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate 98 (PMA)/ionomycin, respectively (3). However, Prasad et al. (2003) found that stimulation of 99 mouse B cells with LPS, IL-4, anti-IgM, or anti-CD40 all downregulated B7-H4 (2). Lee et al. 100 (2012) reported that B7-H4 expression was not observed on human or mouse dendritic cells, 101 monocytes, macrophages, B cells, or T cells, regardless of stimulation (15). These differences 102 may be due to the use of different antibodies for B7-H4 recognition, or differences between 103 mouse and human biology. 104 105 B7-H4 in innate immunity 106 B7-H4 expression has been reported on a highly immunosuppressive subset of tumor- 107 infiltrating macrophages in ovarian cancer and can be induced on macrophages by stimulation 108 with IL-10 and IL-6 (21). Immunosuppressive B7-H4+ tumor-associated macrophages have also 109 been observed in patients with glioma (22). Ex vivo stimulation of mouse macrophages with IL- 110 10 and TGF-β increased B7-H4 expression, and transfusion of these macrophages protected mice 111 from adriamycin nephrosis (23). B7-H4 expression was STAT3-dependent (22) and blockade of 112 both IL-10 and IL-6 (22,24), or stimulation with GM-CSF and IL-4 (21), reduced B7-H4 113 expression. These data indicate that a number of stimuli can regulate B7-H4 expression (Figure 114 2). 115 Macrophages isolated from ovarian tumors or malignant ascites expressed significantly 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 21, 2017; DOI: 10.1158/1078-0432.CCR-15-2440 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 116 higher B7-H4 levels compared to monocytes from normal blood or macrophages from non- 117 malignant ascites (21). B7-H4+ macrophages were 2- to 6-fold more potent than B7-H4- 118 macrophages at suppressing T cell proliferation despite similar levels of activation marker 119 expression and cytokine production (21) Blockade (21,23,25) or knockdown (22) of B7-H4 120 neutralized the suppressive capacity of these macrophages.
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