Inhibitory Receptor Agonists: the Future of Autoimmune Disease Therapeutics?
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Available online at www.sciencedirect.com ScienceDirect Inhibitory receptor agonists: the future of autoimmune disease therapeutics? 1,2 1 Stephanie Grebinoski and Dario AA Vignali + Central and peripheral tolerance both contribute to protection Tregs, implying that >30% of CD4 effectors could be against autoimmunity. The pathogenesis of autoimmunity, autoreactive [2 ]. Critical deficits or limitations in toler- however, can result from critical deficits or limitations in ance mechanisms, rather than complete failure, can con- peripheral and/or central tolerance mechanisms, presenting an tribute to autoimmunity (Figure 1). Evidence suggests opportunity for therapeutic intervention. Recent advances that the majority of these deficits affect peripheral toler- highlight the substantial impact of inhibitory receptors (IRs), ance, presenting an opportunity for therapeutic interven- which mediate peripheral tolerance, in autoimmunity. Deletion tion [1]. and blockade studies in mice, IR disruption in humans, and correlation with positive disease outcomes all highlight Recent advances in cancer immunotherapy indicate that IR potential clinical benefits of enhancing IR signaling modulation affects T cell function and disease outcome, (agonism) — specifically CTLA4, PD1, LAG3, TIM3 and which merited the 2018 Nobel Prize in Medicine [3]. IRs TIGIT — to treat autoimmune disease. Although critical mediateperipheral tolerance byantagonizing T cell receptor questions remain, IR agonists represent an unappreciated and (TCR) signaling and/or signal propagation in autoreactive T untapped opportunity for the treatment of autoimmune and cells, resulting in a dysfunctional state [4]. Evolutionarily, inflammatory diseases. IRs are upregulated in response TCR signaling to dampen the immune response post infection or upon recognition of Addresses self-antigen(Figure1). Under chronic conditions, IR expres- 1 Department of Immunology, University of Pittsburgh School of sion is heightened and T cell effector function is inhibited Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA 2 [5]. Furthermore, evidence suggests that IRs are often Graduate Program of Microbiology and Immunology, University of upregulated as a module (i.e. multiple IRs at the same time), Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA implying cooperative and/or synergistic activity [6 ]. IRs have multiple ligands and different signaling mechanisms Corresponding author: Vignali, Dario AA ([email protected]) (reviewed in [7–9]), but overall result in dampening immune activation. An increasing appreciation for the role of IRs in Current Opinion in Immunology 2020, 67:xx–yy autoimmunity suggests that IR agonism (increasing inhibi- tory signaling and its downstream consequences) may help This review comes from a themed issue on Autoimmunity prevent and manage autoimmune disease (Tables 1–3). Edited by Antonio LaCava Such evidence is exemplified by deletion or blockade stud- ies in mice, outcomes of IR disruption in humans, and positive correlation of IR expression with favorable disease https://doi.org/10.1016/j.coi.2020.06.001 outcomes. This review briefly summarizes the current state of the field in understanding the role ofIRsin autoimmunity, 0952-7915/ã 2020 Elsevier Ltd. All rights reserved. with a focus on the IRs currently in clinical research: cyto- toxic T-lymphocyte-associated protein 4 (CTLA4), Pro- gramed cell death protein 1 (PD1), Lymphocyte Activating Gene 3 (LAG3), T cell immunoglobulin and mucin domain- containing protein 3 (TIM3), and T cell immunoreceptor Introduction with Ig and ITIM domains (TIGIT). Multiple mechanisms of self-tolerance protect against autoimmunity, including central and peripheral toler- Genetic deletion and antibody blockade ance. While central tolerance is critical to delete cells studies in mice expressing autoreactive B and T cell receptors, it is often Some of the most compelling evidence for the role of IRs imperfect [1]. Peripheral tolerance mechanisms, includ- in autoimmunity comes from genetic deletion or antibody ing ignorance, anergy or apoptosis, and regulatory T cells blockade studies. Under non-autoimmune prone condi- (Tregs), are therefore necessary to restrain autoreactivity tions, genetic ablation of either CTLA4 or PD1 results in + À [1]. Recent reports estimate up to 30% CD4 Foxp3 development of spontaneous autoimmune symptoms, cells in healthy mice are able to respond to ‘self’ but are albeit with slightly different manifestations. Mice defi- restrained by Tregs, and posits a compensatory role for cient in CTLA4 rapidly develop severe lymphoprolifera- inhibitory receptor (IR) expression in their model lacking tive disease resulting in death by 3–4 weeks of age, www.sciencedirect.com Current Opinion in Immunology 2020, 67:1–9 2 Autoimmunity Figure 1 Current Opinion in Immunology The role of IRs under normal conditions is to limit TCR signaling and terminate an immune response post-infection or to self-antigen. In autoimmune conditions, IRs are present and limit autoimmunity, but are ultimately insufficient to completely prevent autoimmunity, opening up an opportunity for therapeutic intervention. If IR expression or signaling and subsequent downstream effects is enforced therapeutically, autoimmunity may be prevented or managed more easily by patients. whereas PD1-deficient mice develop lupus-like symp- deleting IRs exacerbates disease in autoimmune-prone toms over time, implying non-redundant functions in backgrounds or induced disease models (reviewed in maintenance of immune tolerance [10–12]. These data [15]). For example, in the non-obese diabetic (NOD) illustrate that simply eliminating PD1 or CTLA4 is mouse model of autoimmune diabetes, a spontaneous sufficient to disrupt baseline immune homeostasis model in which 80% of female mice develop diabetes and maintenance of peripheral tolerance. Alternatively, between 10 and 30 weeks of age, treatment with anti- while genetic ablation of either LAG3, TIGIT or TIM3 PD1 or anti-LAG3 induces autoimmune diabetes with in mice does not precipitate spontaneous autoimmu- 100% penetrance within only a few weeks post administra- nity, LAG3/PD1 double-knockout (KO) mice experi- tion, regardless of timing [16]. Similar results are obtained ence multiple organ autoimmunity that manifests more in global PD1, LAG3 or CTLA4 KOs on a NOD back- aggressively than PD1 KO alone, suggesting a syner- ground [16–20]. Conceptually, these results are mirrored on gistic effect in limiting autoimmunity [13,14]. This the MRL-lpr background, which is susceptible to sponta- difference in disease progression and manifestation neous lupus-like autoimmunity. On the MRL-lpr back- highlights the complexity of targeting each IR in a ground, PD1, CTLA4 and B-lymphocyte and T-lympho- disease setting, the hierarchy of importance in limiting cyte attenuator (BTLA) have been shown to limit disease autoreactivity beginning with CTLA4 and PD1, and progression in studies with KO mice and/or antibody possible synergistic effects of ‘tertiary’ IRs such as blockade [15,21]. LAG3, TIGIT and TIM3. Additionally, IR blockade or deletion worsens autoimmu- Regardless of their role in baseline immune homeostasis or nity in inducible settings. Studies using the experimental spontaneous autoimmunity, blocking or genetically autoimmune encephalomyelitis model (EAE; a mouse Current Opinion in Immunology 2020, 67:1–9 www.sciencedirect.com Inhibitory receptor agonists Grebinoski and Vignali 3 Table 1 Table 2 IR agonists showing therapeutic efficacy in mouse models of IR reinforcement studies that will be translated to treat autoim- autoimmunity. mune patients. Enforcing IR engagement in autoimmune mouse models in vivo Observations that may be translated to autoimmune disease IR Method of Disease setting Ref. IR Method of Setting studied Ref. targeted reinforcement targeted reinforcement PD1 Dendritic cells Improved EAE outcomes [53] LAG3 FGL1-Ig suppresses T Treatment with FGL1-ig [63] transduced to expressed cell proliferation in prevents Lag3+ T cell MHC carrying MOG, vitro activation PDL1, and Trail. Crosslinking LAG3 Cross-linking prevents [64] Adenovirus expressing Suppresses lupus [54] with CD3 prevented T activation of human PBMC PDL1 + ICOS inhibitor symptoms in disease cell activation prone BXSB mice LAG3 agonist Prevents activation of [65] Adenovirus expressing Ameliorates DSS Colitis [55] antibody IMP761 human PBMC, and delayed PDL1-Fc type hypersensitivity in PDL1-Ig Fusion Ameliorates T cell [55] cynomolgus macaque recombinant proteins mediated Colitis TIGIT Agonist anti-TIGIT Decreases proliferation and [66] PDL1-Fc fusion protein PDL1-fc prevented [56] cytokine production in vitro activation in synovial from CD4+ T cells collected fluid mononuclear cells from MS patients of RA patients and FGL1, fibrinogen-like protein 1; PBMC, peripheral blood mononuclear ameliorated CIA cells; MS, multiple sclerosis. PDL1-Ig fusion protein Ameliorated CIA [57] PDL1-Ig fusion protein Improves Islet [58] + anti-CD154 transplantation tolerance Treg-restricted deletion of LAG3 improves disease out- CTLA4 Transgenic mouse Protects NOD mice from [59] comes in autoimmune diabetes, as LAG3 was shown to expressing membrane autoimmune diabetes bound agonist anti- onset limit Treg proliferation in this disease setting [29 ]. CTLA4 on B cells TIM3 Galectin-9 (ligand for Ameliorates CIA [60] Finally, the timing of IR blockade administration or induc- TIM3) was administered tion of IR deletion can give rise to differing disease