Ex vivo assessment of in vivo DC-targeted antibodies in pre-clinical models

CHAPTER TWENTY-ONE

Ex vivo assessment of in vivo DC-targeted antibodies in pre-clinical models Qingrong Huanga,b, Niroshana Anandasabapathya,b,* a

Department of Dermatology, Weill Cornell Medical College, New York, NY, United States Meyer Cancer Center, Weill Cornell Medical College, New York, NY, United States *Corresponding author: e-mail address: [email protected] b

Contents 1. Introduction 2. Antigen presentation and DCs 2.1 Models of antigen presentation: An overview 3. Monitoring receptor-mediated antigen uptake in vivo 4. Protocol for anti-CD205-mediated antigen uptake in vivo 4.1 Materials 4.2 Reagents 4.3 Process Acknowledgments References

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Abstract APCs play a key role at initiating adaptive immune responses by presenting antigens to lymphocytes and DCs are professional APCs. It is critical to understand the differential antigen capture and presentation ability of different DC subsets, which is important for DC-targeted immunotherapy. In this section, we give a brief introduction to different antigen presentation pathways and introduce the key concept of cross-presentation, the major antigen presentation pathway used for anti-viral and anti-tumoral immune responses. CD205, a DC restricted receptor, is highly expressed on certain DCs subsets. We find CD205-mediated antigen uptake to be a useful model for studying antigen uptake and defects. These methods provide an introduction to CD205-mediated preclinical delivery of antigens to cross-presenting DCs, which can be adapted to the study of targeting to multiple receptors and other C-type lectins. This is a promising strategy to detect the antigen capture capacity and to study the key players orchestrating tolerance and immunity ex vivo.

Methods in Enzymology, Volume 632 ISSN 0076-6879 https://doi.org/10.1016/bs.mie.2019.11.007

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2020 Elsevier Inc. All rights reserved.

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1. Introduction Antigen-presenting cells (APCs) are a heterogeneous group of cells that include macrophages, B cells, dendritic cells (DCs). These specialized populations initiate adaptive immune responses by presenting antigens captured from the environment to B and T lymphocytes. Differences in antigen capture ability have been reported among APC types and subsets, and multiple strategies aim to deliver antigens directly to one or more APC subsets in order to expand immune priming. In this section, we will briefly review the antigen presentation pathway, focusing on cross-presentation—the major mechanism by which DCs present tumor and viral antigens. We will then address a strategy to deliver antigens to cross-presenting DCs in a pre-clinical setting, which can be adapted to other DCs or myeloid subsets. Direct delivery of antigens to specific APC subsets is an effective method—proven both to dampen and to expand a T cell driven immune response and to regulate antibody responses (Cheong et al., 2010; Hawiger et al., 2004; Kastenmuller et al., 2014; Tesfaye et al., 2019). In the absence of immune adjuvants targeted immunization can drive tolerance to selfantigens (Hawiger et al., 2004). When instead antigens are administered with an appropriate licensing stimuli, targeted immunization can increase the efficacy of immunization. The targeting methodology can also be used to evaluate the contribution of antigen presentation to specific APC subsets. As such, we have found this to be a helpful strategy to evaluate subset specialization, adjuvant efficacy and routes of immunization (Anandasabapathy et al., 2014; Chappell et al., 2014). Reported strategies include delivery of antigens to unique receptors in vivo by directed ligands, using antibodies conjugated to antigen, nanoparticles, lentiviruses, or recombinant adenovirus engineered to contain antigens (Tacken, Torensma, & Figdor, 2006). Given their broad availability, safety, selectivity, high affinity and avidity, mAbs are a highly popular method for antigen-targeting. Steinman and Cohn first found a group of phagocytic cells in 1973, which could prime and activate naı¨ve T cells, in mouse spleen and named them “dendritic” due to common morphology with the dendrites on a neuron or branched arborization on a tree (Steinman & Cohn, 1973; Steinman & Witmer, 1978). DCs are the major professional APC for initiating adaptive T-cell immunity (Steinman, 2010, 2012) and as such are a rationale choice for targeting antigens. Many studies have demonstrated that antigens can be effectively directed to DCs and presented on both major histocompatibility complex class I and II (MHC I and MHC II) molecules.

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When delivered together with co-stimulatory signals or adjuvant to promote maturation of DCs this method is capable of successfully initiating anti-viral and anti-cancer immune responses (Macri et al., 2016; Ueno et al., 2011). To better understand DC-target immunotherapy and vaccinology, studying the in vivo uptake and presentation of antigens by DCs in a pre-clinical is necessary.

2. Antigen presentation and DCs Based on their capacity to activate naı¨ve T cells and their dependence on specific transcription factors in their ontogeny, DCs are subdivided into different subsets including conventional/classical DCs (cDCs), plasmacytoid DCs (pDCs), Langerhans cells and monocyte-derived DCs. Based on differences in function, phenotype markers and tissue localization, these DCs are also divided into migratory DCs (migDCs), which actively traffic and deliver antigens from tissues to draining lymph nodes (LNs), or LN/spleen resident DCs (cDC and pDC), who spend their entire lifespan in the lymphoid organs. Each DC subset has a distinct role in immunity, infection, tumor presentation, or in the maintenance of self-tolerance because of their different intrinsic abilities to capture, process and present antigens on their MHC I and MHC II molecules (Villadangos & Schnorrer, 2007). MigDCs can actively capture and present antigens located in peripheral tissues and transport antigens to the draining lymph nodes. There, they may present antigens directly or transfer those antigens resident CD8 + DCs for presentation. This kind of cooperation between migDCs and resident DC subsets allows for the exploitation of varied functionality between different DC subsets and helps to optimize the capacity of the DCs network in responding to different infections. MigDCs and cDCs also capture protein and particulate antigens arriving at the draining LN through the lymphatics without active transport by a carrier cell. As such the spatio-temporal regulation of DC behavior is complex and needs to be better dissected. As an additional layer of complexity the half-life and turn-over rate of DCs varies both by subset and by location, again highlighting the dynamic and complex spatio-temporal behavior of these populations (Kamath et al., 2002).

2.1 Models of antigen presentation: An overview Three main different antigen-presenting pathways exist, including MHC I, MHC II pathway and cross-presentation pathway. Antigens that are synthesized intracellularly (for example, those from viral or tumor) are presented by MHC I

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molecules to activate cytotoxic CD8+ T cells. Intracellular antigens, are presented by MHC I molecules in the endoplasmic reticulum (ER) after the antigens translocate from the cytosol. These are derived from proteins degraded mainly in the cytosol, including pathogens replicating in the cytoplasm (such as viruses) or endogenous proteins (produced by the cells themselves) (Blum, Wearsch, & Cresswell, 2013; Heath et al., 2004). In contrast, extracellular antigens are presented by MHC II molecules to activate CD4 + T helper cells. Extracellular antigens, which are presented by MHC II molecules in an endocytic and phagocytic pathways, are derived from proteins degraded in the endosomal compartments, including exogenous materials, which are endocytosed from extracellular environment, and endogenous molecules, such as plasma membrane proteins, components of the endocytic pathway and cytosolic proteins which gain access to the endosomes through autophagy. Extracellular antigens can also be presented to stimulate CD8 + T cells via the MHC I pathway; however, this often requires presentation by DCs specialized to take up dying cells. This is required for immunity against viruses that do not infect APCs directly, or against tumor antigens that are not endogenously expressed by DCs. Specific subsets of DCs are particularly adept at this activity termed “cross-presentation.” These DCs who have the unique ability to deliver exogenous antigens to the MHC I molecules are therefore crucial in anti-virus and anti-tumor immune responses. Crosspresentation is critically important to prime CD8+ T cell-mediated primary immune response (Blum et al., 2013). In cross-presenting DCs, MHC II and MHC I cross-presentation pathways might compete for exogenous antigens. The endocytic mechanism involved in internalization of a given antigen could also affect whether it is preferentially delivered to the MHC II pathway or the MHC I cross-presentation pathway. Therefore understanding of the differential modes of antigen capture (by differential endocytic mechanisms and receptors) and the application of an antigen-targeting method will help us better explore the key roles played and balanced by DC subsets to cross-present antigens.

2.1.1 Cross-presentation pathway Cross-presentation is the process by which exogenous antigens are processed and presented in the MHC I pathway (Bevan, 1976a, 1976b). Both in vivo and in vitro studies suggest MHC I-mediated antigen cross-presentation to CD8 + T cells is associated with cell-associated antigens, which are a

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physiological substrate for cross-presentation (Gutierrez-Martinez et al., 2015; Schulz & Reis e Sousa, 2002; Thacker & Janssen, 2012). While multiple APCs are reported to be able to cross-present antigens, DCs are the most efficient cells in vivo at this process (Barrio et al., 2012; Leiriao, del Fresno, & Ardavin, 2012; Milo et al., 2013). DCs are ubiquitous in the tissue, and uniquely able to not only pick up dead cells, but to migrate to the lymph nodes, where they can cross-present cell-associated antigens to CD8 + T cells (Gutierrez-Martinez et al., 2015). The ability of DCs to crosspresent antigens has inspired many studies finding strategies to target DCs, enhance their cross-presentation, and improve anti-tumor and anti-viral immunity for the treatment of cancer or infectious disease. MHC I-mediated antigen cross-presentation pathway contains five basic steps: antigen acquisition, antigen tagging for destruction and proteolysis, antigen transporting to ER, antigen loading to MHC I molecules, antigen-MHC I complexes displaying on the cell surface (Fehres et al., 2014). MHC I-mediated cross-presentation requires the processing and trimming of the endocytosed antigenic proteins. This generally takes place in two pathways: the cytosolic and the vacuolar pathways. In the cytosolic pathway, internalized antigens need to be transferred to the cytosol from the endosomal compartment. They are then degraded by the proteasome, followed by an antigen processing (TAP)-dependent transporting to the ER or endosomes, where final peptide trimming and MHC I-peptide loading take place (Thacker & Janssen, 2012). Studies suggest inhibition of TAP in endosomes or inhibition of endosomal trafficking to the cell membrane abrogates the cross-presentation of soluble OVA (Burgdorf et al., 2008). While the majority of published studies report the cytosolic pathway as the major cross-presentation pathway, there is also substantial evidence indicating antigen cross-presentation in an proteasome- and TAP-independent pathway, through the vacuolar pathway. In the vacuolar pathway, antigens are processed and loaded onto MHC I molecules in the endosomal/lysosomal compartment. This does not require antigens to exit the endosomal compartment. Instead, antigenic proteins are degraded by lysosomal enzymes and peptides are locally generated and trimmed in the endosome. These then further bind onto MHC I molecules directly. The comparatively contribution of the cytosolic and vacuolar pathways to tumor antigen cross-presentation in vivo is not entirely clear however (Embgenbroich & Burgdorf, 2018; Sanchez-Paulete et al., 2017). Further experiments are needed to investigate the relative importance of both pathways in vivo.

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2.1.2 Endocytic pathway Endocytosis involves internalization of the molecules via cell membrane invagination and pinching off to form the early endosome, which then forms the late endosome, and then the lysosome. The endocytosis of extracellular antigens by APCs is mainly achieved through three pathways: receptormediated endocytosis, phagocytosis, and pinocytosis (Fehres et al., 2014). The receptor-mediated endocytosis is a process by which receptors are applied for transferring antigenic proteins from extracellular matrix into the cells. It is known as clathrin-mediated endocytosis, because clathrin is crucial for this cellular process. During this endocytosis pathway, antigens derived from extracellular proteins bind onto specific receptors and then moves into clathrin-coated pit. The clathrin-coated pit gathers and concentrates extracellular antigenic proteins. Different receptors responsible for the receptormediated endocytosis of antigens, such as low density lipoprotein, growth factors, antibodies and so on. When these receptor carrying their respective antigens, reach the clathrin-coated pit, the pit folds inward and then, together with related membrane part, detaches itself from the cell membrane and forms a closed vesicle. These vesicles move antigens inside the cell and mark them at the same time. When the receptor-carried antigens are pathogens, opsonization system would be activated, which means those antigens are tagged for destruction. After opsonization tagging, the clathrin coat is detached to allow the vesicle to merge into early endosomes, which helps to separate the antigens from their receptors. After antigens are separated multiple chemical changes occur within the early endosomes to form late endosomes, which then split into two parts, with one part containing the antigens, and the other part with receptors. The antigens-containing endosome part then combines and merges with lysosomes, which contain multiple digestive enzymes to break up antigenic proteins. The receptors in the other endosome are then recycled and sent back to the cell surface (Kaksonen & Roux, 2018). Phagocytosis is a process by which larger, extracellular, solid particles, such as bacteria are captured into phagosomes. It is sometimes referred to as “cell eating.” It involves the application of larger membrane areas than receptor-mediated endocytosis. Phagocytosis is an active and highly regulated process that involves specific cell surface receptors and signaling cascade. This process is performed only by special types of cells such as macrophages, monocytes, and neutrophils. In mammals, it is largely concerned with the elimination of foreign materials and pathogens. Viruses use phagocytosis to enter cells. Phagocytic cells are usually very specific in the particles they engulf.

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Pinocytosis is a process of internalizing extracellular fluids along with their solute molecules or antigens into pinosomes. It is also referred to as “cell drinking” compared to phagocytosis. In contrast to phagocytosis usually, pinocytic cells are not specific in the molecules they uptake. Pinocytosis includes several unrelated endocytic mechanisms, in which micropinocytosis is the most common reported one. Except for micropinocytosis, there is also a group of pinocytic pathways that use different proteins to coat the endocytic vesicles derived from the plasma membrane. In addition, some pinocytic pathways involve different membrane lipids or lipid-modifying enzymes (Guermonprez et al., 2002). The main differences between phagocytosis and pinocytosis are as follows. First, phagocytosis ingests comparatively large solid particles, like bacteria and amoeboid protozoans, whereas pinocytosis ingests liquid into the cell by budding a small vesicle from the cell membrane. Second, pinocytosis is not substrate-specific and the cell takes in all kinds of surrounding fluids with solutes, while phagocytosis involves specificity in substrate uptake. Third, the purpose of pinocytosis is to uptake of materials, including enzymes, hormones, amino acids, sugars, etc. Phagocytosis is for defensive purpose and ingesting dust, foreign particles, harmful bacteria and viruses and is performed by neutrophils, macrophages, and protozoans. Although there are differences in the efficiency of these pathways among DCs, B cells, and macrophages, macrophages seem to be best at phagocytosis, whereas DCs prefer receptor-mediated endocytosis (Fehres et al., 2014). Furthermore, DC heterogeneity dictates differences in the relative efficiency of processing and presentation after antigen capture which vary by DC subtype and by route. Prior work measured the internalization and presentation capacity of DCs to MHC I and MHC II-restricted T cells by administering OVA to conventional DCs through either receptor-mediated endocytosis, or pinocytosis, or phagocytosis (Kamphorst et al., 2010). They found that CD8 DCs are more efficient than any other type of APCs tested at presenting antigens to MHCII-restricted T cells, irrespective of the route of antigen capture. In contrast, both subsets of splenic DCs are highly effective in cross-presenting antigens to CD8 + T cells. And also, DCs and activated monocytes could cross-present antigens delivered by DEC205-mediated endocytosis and pinocytosis. There are many types of receptors which could mediate endocytosis of antigens, such as B cell receptor (specific for B cells), Fc receptors, heatshock protein receptors, scavenger receptors, and the C-type lection receptors (CLRs). Overall, these receptors mediate internalization of related

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antigens to endosomes. However, the nature of the related endosomes and theirs fate seem to vary for different receptor types involved and finally, also their ability in inducing antigen cross-presentation (Fehres et al., 2014).

3. Monitoring receptor-mediated antigen uptake in vivo Delivering antigens in vivo by coupling them to antibodies specific for unique receptors and pathways of internalization and presentation on DCs is a highly promising approach for conditioning immunogenic or tolerogenic immune responses. However in addition to their use as a means to regulate immune responses, antigen-targeting systems can also be a useful method to investigate the function of DC subsets and the cellular mechanisms involved (Chappell et al., 2014). DCs have a number of specialized receptors for antigen uptake which include Fcγ receptors and the macrophage mannose receptors, typically shared with other cells, and C-type lectins such as CD205, CD207, and CD209, which can be more DC restricted, depending on species. CD205 (DEC-205) is an endocytic receptor reported to have special ability to uptake and subsequently direct antigens to processing and loading onto both MHC II and MHC I molecules (Bonifaz et al., 2002, 2004). CD205 is highly expressed on certain DC subsets including cross-presenting and tissue migratory DCs in mouse (Anandasabapathy et al., 2014). Anti-CD205 has been used to target antigens specifically to DCs in mice (Mukherjee et al., 2013) and is in current use in human cancer clinical trials. Moreover targeting CD205 and other C-type lectins is a useful model by which to study the spatio-temporal regulation of and subset specific antigen capture by DCs. Prior studies using this strategy have highlighted important differences in the kinetic capture ability of DCs present in the draining LN having migrating to the draining LN from peripheral tissues, and those which are always present in the draining LN without having surveyed the tissues (Anandasabapathy et al., 2014). Such differences are linked to important functional outcomes for immunity and tolerance in vivo. To study antigen capture on CD205 in vivo, labeled anti-CD205 antibodies to CD205 receptors on DCs can be used and this method is provided below ( Jiang et al., 1995). Anti-CD205 antibodies are rapidly taken up by receptor-mediated endocytosis into coated pits and vesicles, and then transferred to a multi-vesicular endosomal compartment, which resembles the MHC class II-containing vesicles involved in antigen presentation ( Jiang et al., 1995). CD205 direct antigens to the late endosomes on human

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cross-presenting DCs (Cohn et al., 2013). Anti-CD205 antibodies provide an efficient method for targeting DCs to evaluate receptor-based antigen uptake under various conditions and by different cell types. This is a useful measure of cross-presentation capacity and the study of tolerance in the steady state or immunity when administered with agents to enable DC maturation (Bonifaz et al., 2002).

4. Protocol for anti-CD205-mediated antigen uptake in vivo 4.1 Materials • • • • • • • •

0.5 mL Insulin Syringes with the Micro-Fine™ Needle (28G needle) Six-well plate 10 cm Petri dish 3 mL syringe with 25G needle curved forcep, straight forcep 15 mL conical tube, 50 mL conical tube short Pasteur pipettes with cotton top 70 μm cell strainer

4.2 Reagents • • • • •

Isoflurane Fluorophore conjugated anti-mouse CD205 (DEC-205) Antibody Fluorophore conjugated Isotype Antibody 70% EtOH R5 medium Components of R5 medium

Volume

RPMI

500 mL

FBS

30 mL

L-Glutamine

5 mL

Pen Strep (10,000 U/mL)

5 mL

HEPES (1 M)

5 mL

Gentamicin (10 mg/mL)

2.5 mL

2-Mercaptoethanol (1000 )

500 μL

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1  DPBS Hanks Balanced Salt Solution (HBSS) with Calcium chloride and Magnesium chloride (HBSS +/+) HBSS without Calcium chloride and Magnesium chloride (HBSS / ) CollagenaseD and DNase I 0.5 M EDTA (quenches collagenase and dissociates T cell/DC complexes to enhance the isolation) FACS buffer (1 DPBS with 2% FBS) Anti-CD16/CD32 FC block

4.3 Process (Fig. 1) 4.3.1 Footpad injection • Prepare 2.5 μg antibodies in 100 μL of sterile PBS for each mouse. • Anesthetize mice with isoflurane and give 2.5 μg antibodies to each mouse through footpad injection in 50 μL per footpad. Administer isotype control antibodies to the control group separately in parallel.

4.3.2 Tissue harvest • 1, 3, and 5 h after antibodies injection, harvest popliteal lymph nodes (LNs), inguinal LNs, spleen, brachial LNs, cervical LNs, from each individual mouse. • Put harvested tissues into R5 medium before processing.

Fig. 1 Anti-CD205 antibody is administered by footpad injection. Popliteal and inguinal LNs are harvested and analyzed 3 h later.

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4.3.3 DCs preparation from tissues 4.3.3.1 Spleen and LN

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•

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• •

•

Sacrifice animals, soak in 70% ethanol or spray them with 70% ethanol. Dissect the mice and get LNs and spleen, put them in the individual sixwell plates (contain 5 mL R5 media in each well). Wash and transfer them in new wells of the six-well plates (containing 4.5 mL of HBSS+/+ in each well), add 500 μL collagenase (the final concentration would be 2.5 mg/mL) to each well right before teasing/ballooning. Balloon spleens with medium containing collagenase D. When spleen turns “white,” tease spleen into small pieces. Using curved forceps and 3 mL syringe with a 25 g needle, tease apart LNs into small pieces (in medium containing 2.5 mg/mL collagenase D). Tease very well to the point when no floating pieces of stroma are left. Incubate LNs and spleen at 37 °C (incubator) for 22–28 min (22 min for spleen and 28 min for LN). Use a glass pipet to bulb pipet up and down multiple times, then add 100 μL of 0.5 M EDTA to stop the digestion, pipet up and down again, then swirl dish and put back in incubator for 5 min more. Add a full volume of 2% FACS buffer or R5 medium to stop the EDTA after 5 min. Transfer and filter cells into 15 mL conical tube through 0.7 μm strainer using short cotton glass Pasteur pipet and then spin down at 1500 rpm for 5 min. For LNs, vacuum off supernatant and resuspend the cells in 5 or 10 mL R5 medium. For the spleen, vacuum off supernatant and resuspend in 1 mL ACK lysis buffer (each spleen), lysis for 15 s, then add FACS buffer to stop the lysis, spin at 1500 rpm for 5 min. Vacuum supernatant and resuspend in 10 mL R5 medium. Count the cells from LN and spleen.

4.3.4 DCs staining to check antigen uptake through flow cytometry analysis 4.3.4.1 Surface marker staining

• •

Plate the cells into a 96-well plate V bottom plate for staining on ice in PBS or FACS buffer as indicated. Staining cocktail should leave the fluorophore channel empty which was used for antibody targeting.

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250 μL staining system, up to 5  106 cells (the most) per 250 μL. Wash cells twice with PBS. Stain cells with aqua (11000) dilution in PBS for 30 min on ice. Wash with DPBS once and then with FACS buffer once. Block the cells in FC block (anti-CD16/CD32, 1:200), 250 μL/each well, and Incubate in FC block for 20–25 min. Wash with FACS twice. Prepare staining cocktail in FACS buffer and incubate stained cells for 45 min on ice. Wash cells with FACS buffer twice. Fix the cells using BD Fix/Perm for 10 min on ice (100 L/per well). Wash cells with BD 1 Perm/wash buffer, twice. For the spleen and LN, resuspend cells in FACS, transfer cells to FACS tube.

4.3.4.2 Intracellular marker staining

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After the surface marker staining mentioned above. Wash cells with 1  BD Perm/wash buffer twice. Prepare intracellular staining cocktail in 1  BD Perm/wash buffer and incubate cells for 30 min on ice. Wash twice with 1  BD Perm/wash buffer. Resuspend cells in FACS, and then transfer cells to FACS tube. Running samples and analyze the data. Compare the relative antigen capture of anti-CD205 antibody to isotype control by site specific uptake for each.

Acknowledgments The authors are grateful to the ongoing wisdom of Ralph M. Steinman whose passion for Dendritic Cells was contagious.

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