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3. CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity

Author

Gressier, Elise, Schulte-Schrepping, Jonas, Petrov, Lev, Brumhard, Sophia, Stubbemann, Paula, Hiller, Anna, Obermayer, Benedikt, Spitzer, Jasper, Kostevc, Tomislav, Whitney, Paul G., Bachem, Annabell, Odainic, Alexandru, van de Sandt, Carolien, Nguyen, Thi H. O., Ashhurst, Thomas, Wilson, Kayla, Oates, Clare V. L., Gearing, Linden. J., Meischel, Tina, Hochheiser, Katharina, Greyer, Marie, Clarke, Michele, Kreutzenbeck, Maike, Gabriel, Sarah S., Kastenmüller, Wolfgang, Kurts, Christian, Londrigan, Sarah L., Kallies, Axel, Kedzierska, Katherine, Hertzog, Paul J., Latz, Eicke, Chen, Yu-Chen E., Radford, Kristen J., Chopin, Michael, Schroeder, Jan, Kurth, Florian, Gebhardt, Thomas, Sander, Leif E., Sawitzki, Birgit, Schultze, Joachim L., Schmidt, Susanne V., and Bedoui, Sammy

Published
2023
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5. Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells

Author

Masterman, Kelly-Anne, Haigh, Oscar L, Tullett, Kirsteen M, Leal-Rojas, Ingrid M, Walpole, Carina, Pearson, Frances E, Cebon, Jonathon, Schmidt, Christopher, O'Brien, Liam, Rosendahl, Nikita, Daraj, Ghazal, Caminschi, Irina, Gschweng, Eric H, Hollis, Roger P, Kohn, Donald B, Lahoud, Mireille H, and Radford, Kristen J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Immunization, Prevention, Biotechnology, Vaccine Related, Clinical Research, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Dendritic Cells, Female, Healthy Volunteers, Humans, Lectins, C-Type, Membrane Proteins, Mice, Receptors, Mitogen, Thrombomodulin, dendritic cells, immunogenicity, vaccine, immunotherapy, melanoma, Oncology and carcinogenesis
Abstract

Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells. CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.

Published
2020

12. Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection

Author

Sikder, Md. Al Amin, primary, Rashid, Ridwan B., additional, Ahmed, Tufael, additional, Sebina, Ismail, additional, Howard, Daniel R., additional, Ullah, Md. Ashik, additional, Rahman, Muhammed Mahfuzur, additional, Lynch, Jason P., additional, Curren, Bodie, additional, Werder, Rhiannon B., additional, Simpson, Jennifer, additional, Bissell, Alec, additional, Morrison, Mark, additional, Walpole, Carina, additional, Radford, Kristen J., additional, Kumar, Vinod, additional, Woodruff, Trent M., additional, Ying, Tan Hui, additional, Ali, Ayesha, additional, Kaiko, Gerard E., additional, Upham, John W., additional, Hoelzle, Robert D., additional, Cuív, Páraic Ó., additional, Holt, Patrick G., additional, Dennis, Paul G., additional, and Phipps, Simon, additional

Published
2023
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13. The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis

Author

Sikder, Md. Al Amin, primary, Rashid, Ridwan B., additional, Ahmed, Tufael, additional, Sebina, Ismail, additional, Howard, Daniel, additional, Ullah, Md. Ashik, additional, Rahman, Muhammed Mahfuzur, additional, Lynch, Jason P., additional, Curren, Bodie, additional, Werder, Rhiannon B., additional, Simpson, Jennifer, additional, Bissell, Alec, additional, Morrison, Mark, additional, Walpole, Carina, additional, Radford, Kristen J., additional, Kumar, Vinod, additional, Woodruff, Trent M., additional, HuiYing, Tan, additional, Ali, Ayesha, additional, Kaiko, Gerard E., additional, Upham, John W., additional, Hoelzle, Robert D., additional, Cuív, Páraic Ó, additional, Holt, Patrick G., additional, Dennis, Paul G., additional, and Phipps, Simon, additional

Published
2023
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14. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells

Author

Leung, Sherman S., primary, Borg, Danielle J., primary, McCarthy, Domenica A., primary, Boursalian, Tamar E., primary, Cracraft, Justen, primary, Zhuang, Aowen, primary, Fotheringham, Amelia K., primary, Flemming, Nicole, primary, Watkins, Thomas, primary, Miles, John J., primary, Groop, Per-Henrik, primary, Scheijen, Jean L., primary, Schalkwijk, Casper G., primary, Steptoe, Raymond J., primary, Radford, Kristen J., primary, Knip, Mikael, primary, and Forbes, Josephine M., primary

Published
2022
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15. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

Author

Beringer, Dennis X, Kleijwegt, Fleur S, Wiede, Florian, van der Slik, Arno R, Loh, Khai Lee, Petersen, Jan, Dudek, Nadine L, Duinkerken, Gaby, Laban, Sandra, Joosten, Antoinette, Vivian, Julian P, Chen, Zhenjun, Uldrich, Adam P, Godfrey, Dale I, McCluskey, James, Price, David A, Radford, Kristen J, Purcell, Anthony W, Nikolic, Tatjana, Reid, Hugh H, Tiganis, Tony, Roep, Bart O, and Rossjohn, Jamie

Published
2015
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18. Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Author

Pang, Ee Shan, primary, Daraj, Ghazal, additional, Balka, Katherine R., additional, De Nardo, Dominic, additional, Macri, Christophe, additional, Hochrein, Hubertus, additional, Masterman, Kelly-Anne, additional, Tan, Peck S., additional, Shoppee, Angus, additional, Magill, Zoe, additional, Jahan, Nazneen, additional, Bafit, Mariam, additional, Zhan, Yifan, additional, Kile, Benjamin T., additional, Lawlor, Kate E., additional, Radford, Kristen J., additional, Wright, Mark D., additional, and O’Keeffe, Meredith, additional

Published
2022
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21. Elucidating the Motif for CpG Oligonucleotide Binding to the Dendritic Cell Receptor DEC-205 Leads to Improved Adjuvants for Liver-Resident Memory

Author

Li, Jessica, primary, Panetta, Fatma, additional, O’Keeffe, Meredith, additional, Leal Rojas, Ingrid M., additional, Radford, Kristen J., additional, Zhang, Jian-Guo, additional, Fernandez-Ruiz, Daniel, additional, Davey, Gayle M., additional, Gully, Benjamin S., additional, Tullett, Kirsteen M., additional, Rossjohn, Jamie, additional, Berry, Richard, additional, Lee, Chin-Nien, additional, Lahoud, Mireille H., additional, Heath, William R., additional, and Caminschi, Irina, additional

Published
2021
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22. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells.

Author

Leung, Sherman S., Borg, Danielle J., McCarthy, Domenica A., Boursalian, Tamar E., Cracraft, Justen, Zhuang, Aowen, Fotheringham, Amelia K., Flemming, Nicole, Watkins, Thomas, Miles, John J., Groop, Per-Henrik, Scheijen, Jean L., Schalkwijk, Casper G., Steptoe, Raymond J., Radford, Kristen J., Knip, Mikael, and Forbes, Josephine M.

Subjects
INSULIN therapy, RESEARCH evaluation, ANIMAL experimentation, TYPE 1 diabetes, AUTOIMMUNE diseases, T cells, MICE
Abstract

Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells. [ABSTRACT FROM AUTHOR]

Published
2022
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23. T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

Author

Forbes, Josephine M., McCarthy, Domenica A., Kassianos, Andrew J, Baskerville, Tracey, Fotheringham, Amelia K., Giuliani, Kurt T.K., Grivei, Anca, Murphy, Andrew J., Flynn, Michelle C., Sullivan, Mitchell A., Chandrashekar, Preeti, Whiddett, Rani, Radford, Kristen J., Flemming, Nicole, Beard, Sam S., D'Silva, Neisha, Nisbet, Janelle, Morton, Adam, Teasdale, Stephanie, Russell, Anthony, Isbel, Nicole, Jones, Timothy, Couper, Jennifer, Healy, Helen, Harris, Mark, Donaghue, Kim, Johnson, David W., Cotterill, Andrew, Barrett, Helen L., O'Moore-Sullivan, Trisha, Forbes, Josephine M., McCarthy, Domenica A., Kassianos, Andrew J, Baskerville, Tracey, Fotheringham, Amelia K., Giuliani, Kurt T.K., Grivei, Anca, Murphy, Andrew J., Flynn, Michelle C., Sullivan, Mitchell A., Chandrashekar, Preeti, Whiddett, Rani, Radford, Kristen J., Flemming, Nicole, Beard, Sam S., D'Silva, Neisha, Nisbet, Janelle, Morton, Adam, Teasdale, Stephanie, Russell, Anthony, Isbel, Nicole, Jones, Timothy, Couper, Jennifer, Healy, Helen, Harris, Mark, Donaghue, Kim, Johnson, David W., Cotterill, Andrew, Barrett, Helen L., and O'Moore-Sullivan, Trisha

Abstract

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E−/− mice. Kidney biopsies were used to examine infiltration of KIM-1–expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0–10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes sho

Published
2021

25. CD4+T cell calibration of antigen-presenting cells optimizes antiviral CD8+T cell immunity

Author

Gressier, Elise, Schulte-Schrepping, Jonas, Petrov, Lev, Brumhard, Sophia, Stubbemann, Paula, Hiller, Anna, Obermayer, Benedikt, Spitzer, Jasper, Kostevc, Tomislav, Whitney, Paul G., Bachem, Annabell, Odainic, Alexandru, van de Sandt, Carolien, Nguyen, Thi H. O., Ashhurst, Thomas, Wilson, Kayla, Oates, Clare V. L., Gearing, Linden. J., Meischel, Tina, Hochheiser, Katharina, Greyer, Marie, Clarke, Michele, Kreutzenbeck, Maike, Gabriel, Sarah S., Kastenmüller, Wolfgang, Kurts, Christian, Londrigan, Sarah L., Kallies, Axel, Kedzierska, Katherine, Hertzog, Paul J., Latz, Eicke, Chen, Yu-Chen E., Radford, Kristen J., Chopin, Michael, Schroeder, Jan, Kurth, Florian, Gebhardt, Thomas, Sander, Leif E., Sawitzki, Birgit, Schultze, Joachim L., Schmidt, Susanne V., and Bedoui, Sammy

Abstract

Antiviral CD8+T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. These responses are critical for the acquisition of antiviral CD8+T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+T cells to select the innate circuits that guide antiviral CD8+T cell responses.

Published
2023
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26. T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

Author

Forbes, Josephine M., primary, McCarthy, Domenica A., additional, Kassianos, Andrew J., additional, Baskerville, Tracey, additional, Fotheringham, Amelia K., additional, Giuliani, Kurt T.K., additional, Grivei, Anca, additional, Murphy, Andrew J., additional, Flynn, Michelle C., additional, Sullivan, Mitchell A., additional, Chandrashekar, Preeti, additional, Whiddett, Rani, additional, Radford, Kristen J., additional, Flemming, Nicole, additional, Beard, Sam S., additional, D’Silva, Neisha, additional, Nisbet, Janelle, additional, Morton, Adam, additional, Teasdale, Stephanie, additional, Russell, Anthony, additional, Isbel, Nicole, additional, Jones, Timothy, additional, Couper, Jennifer, additional, Healy, Helen, additional, Harris, Mark, additional, Donaghue, Kim, additional, Johnson, David W., additional, Cotterill, Andrew, additional, Barrett, Helen L., additional, and O’Moore-Sullivan, Trisha, additional

Published
2021
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29. RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells

Author

Tullett, Kirsteen M, primary, Tan, Peck Szee, additional, Park, Hae-Young, additional, Schittenhelm, Ralf B, additional, Michael, Nicole, additional, Li, Rong, additional, Policheni, Antonia N, additional, Gruber, Emily, additional, Huang, Cheng, additional, Fulcher, Alex J, additional, Danne, Jillian C, additional, Czabotar, Peter E, additional, Wakim, Linda M, additional, Mintern, Justine D, additional, Ramm, Georg, additional, Radford, Kristen J, additional, Caminschi, Irina, additional, O'Keeffe, Meredith, additional, Villadangos, Jose A, additional, Wright, Mark D, additional, Blewitt, Marnie E, additional, Heath, William R, additional, Shortman, Ken, additional, Purcell, Anthony W, additional, Nicola, Nicos A, additional, Zhang, Jian-Guo, additional, and Lahoud, Mireille H, additional

Published
2020
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35. Author response: RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells

Author

Tullett, Kirsteen M, primary, Tan, Peck Szee, additional, Park, Hae-Young, additional, Schittenhelm, Ralf B, additional, Michael, Nicole, additional, Li, Rong, additional, Policheni, Antonia N, additional, Gruber, Emily, additional, Huang, Cheng, additional, Fulcher, Alex J, additional, Danne, Jillian C, additional, Czabotar, Peter E, additional, Wakim, Linda M, additional, Mintern, Justine D, additional, Ramm, Georg, additional, Radford, Kristen J, additional, Caminschi, Irina, additional, O'Keeffe, Meredith, additional, Villadangos, Jose A, additional, Wright, Mark D, additional, Blewitt, Marnie E, additional, Heath, William R, additional, Shortman, Ken, additional, Purcell, Anthony W, additional, Nicola, Nicos A, additional, Zhang, Jian-Guo, additional, and Lahoud, Mireille H, additional

Published
2020
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36. Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

Author

Leung, Sherman S., primary, Borg, Danielle J., additional, McCarthy, Domenica A., additional, Boursalian, Tamar E., additional, Cracraft, Justen, additional, Zhuang, Aowen, additional, Fotheringham, Amelia K., additional, Flemming, Nicole, additional, Watkins, Thomas, additional, Miles, John J., additional, Groop, Per-Henrik, additional, Scheijen, Jean L., additional, Schalkwijk, Casper G., additional, Steptoe, Raymond J., additional, Radford, Kristen J., additional, Knip, Mikael, additional, and Forbes, Josephine M., additional

Published
2020
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37. Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells

Author

Pearson, Frances E, primary, Tullett, Kirsteen M, additional, Leal‐Rojas, Ingrid M, additional, Haigh, Oscar L, additional, Masterman, Kelly‐Anne, additional, Walpole, Carina, additional, Bridgeman, John S, additional, McLaren, James E, additional, Ladell, Kristin, additional, Miners, Kelly, additional, Llewellyn‐Lacey, Sian, additional, Price, David A, additional, Tunger, Antje, additional, Schmitz, Marc, additional, Miles, John J, additional, Lahoud, Mireille H, additional, and Radford, Kristen J, additional

Published
2020
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41. Conventional type 1 dendritic cells (cDC1) as cancer therapeutics: challenges and opportunities

Author

Johnson, Phillip, Rosendahl, Nikita, and Radford, Kristen J

Abstract

ABSTRACTIntroductionThe use of dendritic cell (DC)-based cancer vaccines over three decades has shown them to be a safe therapeutic approach against a range of hematological and solid malignancies. However, underwhelming and inconsistent results from clinical trials have seen them move in and out of favor. The limitations of ex vivogenerated monocyte-derived DC (MoDC) in these therapies provide a pointed explanation for the varying and somewhat disappointing clinical outcomes. The identification of a specialized role for the rare conventional type 1 dendritic cell (cDC1) subset in orchestrating tumor immunity via the initiation of CD8+ T cell responses has led to a new concept of targeting cDC1 as a therapeutic option to address the unmet need of enhancing the immune response in cancer patients.Areas CoveredThis article reviews several current challenges and key opportunities associated with the development and use of next generation cDC1 cancer vaccines.Expert OpinionManipulation of cDC1 quantity and quality holds enormous potential to improve tumor immunogenicity, as already demonstrated in preclinical models. New technologies are rapidly advancing the understanding of cDC1 in human cancer patients and facilitating the generation of these extremely rare cells in vitro, providing feasible new approaches toward clinical translation.

Published
2022
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44. Chapter Two: Unexplored horizons of cDC1 in immunity and tolerance.

Author

Balan, Sreekumar, Radford, Kristen J., and Bhardwaj, Nina

Subjects
CYTOTOXIC T cells, HUMAN biology, DENDRITIC cells, IMMUNITY
Abstract

Dendritic cells are a specialized subset of hematopoietic cells essential for mounting immunity against tumors and infectious disease as well as inducing tolerance for maintenance of homeostasis. DCs are equipped with number of immunoregulatory or stimulatory molecules that interact with other leukocytes to modulate their functions. Recent advances in DC biology identified a specific role for the conventional dendritic cell type 1 (cDC1) in eliciting cytotoxic CD8+ T cells essential for clearance of tumors and infected cells. The critical role of this subset in eliciting immune responses or inducing tolerance has largely been defined in mice whereas the biology of human cDC1 is poorly characterized owing to their extremely low frequency in tissues. A detailed characterization of the functions of many immunoregulatory and stimulatory molecules expressed by human cDC1 is critical for understanding their biology to exploit this subset for designing novel therapeutic modalities against cancer, infectious disease and autoimmune disorders. [ABSTRACT FROM AUTHOR]

Published
2020
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45. Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells.

Author

Pearson, Frances E, Tullett, Kirsteen M, Leal‐Rojas, Ingrid M, Haigh, Oscar L, Masterman, Kelly‐Anne, Walpole, Carina, Bridgeman, John S, McLaren, James E, Ladell, Kristin, Miners, Kelly, Llewellyn‐Lacey, Sian, Price, David A, Tunger, Antje, Schmitz, Marc, Miles, John J, Lahoud, Mireille H, and Radford, Kristen J

Subjects
NEPHROBLASTOMA, T cells, DENDRITIC cells, IMMUNOGLOBULINS, ANTIGENS, HYPERCOAGULATION disorders
Abstract

Objectives: Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods: WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results: The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions: Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1. [ABSTRACT FROM AUTHOR]

Published
2020
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