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Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. 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Aaron Ring received his undergraduate training at Yale University and entered the Stanford Medical Scientist Training Program for his MD and PhD degrees. At Stanford, he worked in the laboratories of K. Christopher Garcia and Irving Weissman to use structure-based protein engineering to develop new cytokine and immune checkpoint therapies for cancer. Aaron joined the faculty of the Yale Department of Immunobiology in 2016 as the Robert T. McCluskey Yale Scholar. The focus of his research is to understand and manipulate the activity of immune receptors using precision immunopharmacology and systems immunology.

\",\"photo\":{\"hiResUrl\":\"https://files-profile.medicine.yale.edu/images/689fe8c3-0dd9-46b8-afa9-c8c667ec703e\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/689fe8c3-0dd9-46b8-afa9-c8c667ec703e\",\"altText\":\"Aaron Ring\",\"width\":2000,\"height\":3000,\"imageVariants\":[{\"dimension\":\"Square\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/4ce857ad-acb7-4e7a-8ac7-90a8d651e166\",\"width\":2000,\"height\":2000},{\"dimension\":\"Rectangle\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/1ab267b0-bcb9-4296-aff0-76061cffb956\",\"width\":2000,\"height\":2500}]},\"gallery\":null,\"organizations\":[{\"id\":110443,\"name\":\"Cancer Immunology\",\"url\":\"https://medicine.yale.edu/cancer/research/people/immunology.aspx\"},{\"id\":108794,\"name\":\"Immunobiology\",\"url\":\"http://immunobiology.yale.edu\"},{\"id\":109534,\"name\":\"Immunology\",\"url\":\"http://bbs.yale.edu/immunology\"},{\"id\":110408,\"name\":\"Molecular Medicine, Pharmacology, and Physiology\",\"url\":\"http://bbs.yale.edu/molmed/index.aspx\"},{\"id\":110300,\"name\":\"Secondary Faculty\",\"url\":null},{\"id\":109631,\"name\":\"Yale Cancer Center\",\"url\":\"https://www.yalecancercenter.org\"},{\"id\":109532,\"name\":\"Yale Combined Program in the Biological and Biomedical Sciences (BBS)\",\"url\":\"http://bbs.yale.edu\"},{\"id\":110762,\"name\":\"Yale University\",\"url\":\"https://www.yale.edu/\"},{\"id\":119405,\"name\":\"Yale-UPR Integrated HIV Basic and Clinical Sciences Initiative\",\"url\":\"https://medicine.yale.edu/yupr/\"}],\"appointmentOrganizations\":[{\"id\":108794,\"name\":\"Immunobiology\",\"url\":\"http://immunobiology.yale.edu\"}],\"educations\":[{\"degree\":\"MD\",\"institution\":\"Stanford University School of Medicine (2016)\"},{\"degree\":\"PhD\",\"institution\":\"Stanford University School of Medicine, Structural Biology (2016)\"},{\"degree\":\"BS\",\"institution\":\"Yale University, Molecular Biophysics and Biochemistry (2008)\"},{\"degree\":\"MS\",\"institution\":\"Yale University, Molecular Biophysics and Biochemistry (2008)\"}],\"honors\":[{\"award\":\"Milstein Young Investigator Award\",\"awardingOrganization\":\"International Cytokine & Interferon Society\",\"date\":\"2020\"},{\"award\":\"Pew-Stewart Scholar\",\"awardingOrganization\":\"The Pew Charitable Trusts\",\"date\":\"2018\"},{\"award\":\"NIH Director's Early Independence Award (DP-5)\",\"awardingOrganization\":null,\"date\":\"2016\"},{\"award\":\"Robert T. McCluskey Yale Scholar\",\"awardingOrganization\":null,\"date\":\"2016\"},{\"award\":\"Forbes 30 under 30 - Healthcare\",\"awardingOrganization\":null,\"date\":\"2016\"},{\"award\":\"Ruth L. Kirschstein National Research Service Award\",\"awardingOrganization\":null,\"date\":\"2011\"},{\"award\":\"Paul Sigler Memorial Award\",\"awardingOrganization\":null,\"date\":\"2008\"},{\"award\":\"Barry Goldwater Scholar\",\"awardingOrganization\":null,\"date\":\"2007\"},{\"award\":\"Beckman Scholar\",\"awardingOrganization\":null,\"date\":\"2006\"}],\"services\":[],\"activities\":[]},\"researchTab\":{\"research\":{\"description\":\"

Our research programs involve pharmacologic dissection of immune signaling pathways as well as developing new tools for systems immunology research.

Immunopharmacology:\\n

1) Engineering cytokines for cancer immunotherapy with directed evolution. Cytokines were the first drugs that proved the immune system could be an ally against cancer, but they have been limited in their therapeutic use due to their biological pleiotropism (having multiple inputs and outputs). We are using directed evolution to create new immune cytokines with precisely defined activities. These “designer” proteins enable fine mechanistic dissection of immune signaling pathways and also offer pharmacologic tools for therapeutic development. As a recent example, we developed a version of IL-18 that is impervious to a tumor-produced “jamming signal” called IL-18BP. We found engineered IL-18 has dramatically increased anti-tumor efficacy in multiple mouse cancer models (Zhou et a., Nature, 2020) and the molecule is now being developed for clinical use, with clinical trials expected to start in 2021. \\n

2) Targeting pathological “necro-inflammation” in autoinflammatory and autoimmune disease. The manner in which a cell dies has a profound influence on the resulting response that occurs when immune cells come into contact with its remains. While some types of cell death are anti-inflammatory, such as apoptosis, others are highly inflammatory, like accidental necrosis or programmed necroptosis and pyroptosis. In collaboration with Andrew Wang’s lab, we have recently discovered a novel receptor for inflammatory cell death that is required for necroinflammation downstream of physiochemical necrosis and necroptosis. We have developed antagonists of this receptor and found that they have a major impact in mouse models of sepsis, pancreatitis, and systemic lupus erythematosus. We are continuing to probe the biology of this novel pathway and have initiated new screens to discover additional sensors for other types of cell death such as ferroptosis and pyroptosis.\\n

Systems Immunology:\\n

1) Mapping the interactome between microbes and the host exoproteome. We are collaborating with Noah’s Palm laboratory to explore host:microbe interactions in commensal and pathobiont microbes using a novel technology we developed called BASEHIT. This platform allows us to identify potential interactions between bacteria and >3,000 extracellular and secreted human proteins (the “exoproteome”). These novel interactions provide new insights into how our microbiota influence our health and disease.\\n

2) Discovering novel autoantibody responses in autoimmune disease and cancer. Autoantibodies are classically associated with contributing to autoimmune disease, however, there is growing recognition that some autoantibody responses have beneficial effects. For instance, cancer patients that make antibodies against tumor proteins have better outcomes. Similarly, autoimmune disease patients that make immunosuppressive anti-cytokine antibodies have less severe disease. Discovering disease-ameliorating antibody responses can thus give insights into potential new therapeutic targets and potentially drugs themselves. To discover functional autoantibody responses, we developed a technology called REAP (Rapid Exoproteome Antigen Profiling) that allows for the comprehensive identification of autoantibody responses to the exoproteome with just a small volume of serum/plasma and in high throughput. We are now applying REAP to numerous diseases, including cancer patients treated with immunotherapy and patients with systemic lupus erythematosus.\\n

3) Comprehensive discovery of ‘nanobodies’ to extracellular and secreted proteins. Single domain antibodies (‘nanobodies’) are powerful research tools and an emerging class of therapeutics. We have created a pipeline to discover and validate nanobodies against thousands of extracellular antigens. We are using the discovered nanobodies as probes for single-cell proteomics and also as open-source pharmacologic tools.\\n

\",\"summary\":\"

The overarching objective of our research is to understand and manipulate the communication circuitry of the immune system using precision immunopharmacology and systems immunology. Specifically, we use directed evolution to create new pharmacologic tools and therapeutics against key immune receptors. Additionally, we have begun to re-purpose the same directed evolution technologies for systems immunology; for example, to discover and profile functional humoral responses that mediate and mitigate disease and to detect novel transkingom interactions between our microbiota and the human exoproteome.\\n

\",\"researchInterests\":[\"Immune System\",\"Neoplasms\",\"Systems Biology\",\"Drug Discovery\",\"Immunomodulation\"],\"healthInterests\":[],\"researchImagesGallery\":null},\"publications\":[{\"title\":\"IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.\",\"citation\":\"Zhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, Fischer S, Jackson R, Flavell RA, Wang J, Sanmamed MF, Bosenberg MW, Ring AM. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020, 583:609-614.\",\"year\":2020,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/32581358\",\"text\":\"IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.\"}},{\"title\":\"Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy.\",\"citation\":\"Chhabra A, Ring AM, Weiskopf K, Schnorr PJ, Gordon S, Le AC, Kwon HS, Ring NG, Volkmer J, Ho PY, Tseng S, Weissman IL, Shizuru JA. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Science Translational Medicine 2016, 8:351ra105.\",\"year\":2016,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/27510901\",\"text\":\"Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy.\"}},{\"title\":\"Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.\",\"citation\":\"Maute RL, Gordon SR, Mayer AT, McCracken MN, Natarajan A, Ring NG, Kimura R, Tsai JM, Manglik A, Kruse AC, Gambhir SS, Weissman IL, Ring AM. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112:E6506-14.\",\"year\":2015,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/26604307\",\"text\":\"Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.\"}},{\"title\":\"Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.\",\"citation\":\"Mitra S, Ring AM, Amarnath S, Spangler JB, Li P, Ju W, Fischer S, Oh J, Spolski R, Weiskopf K, Kohrt H, Foley JE, Rajagopalan S, Long EO, Fowler DH, Waldmann TA, Garcia KC, Leonard WJ. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 2015, 42:826-38.\",\"year\":2015,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/25992859\",\"text\":\"Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.\"}},{\"title\":\"Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.\",\"citation\":\"Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science (New York, N.Y.) 2013, 341:88-91.\",\"year\":2013,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/23722425\",\"text\":\"Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.\"}},{\"title\":\"Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody.\",\"citation\":\"Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK. Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature 2013, 502:575-579.\",\"year\":2013,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/24056936\",\"text\":\"Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody.\"}},{\"title\":\"Activation and allosteric modulation of a muscarinic acetylcholine receptor.\",\"citation\":\"Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 2013, 504:101-6.\",\"year\":2013,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/24256733\",\"text\":\"Activation and allosteric modulation of a muscarinic acetylcholine receptor.\"}},{\"title\":\"Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'.\",\"citation\":\"Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P, Pande VS, Fathman CG, Boyman O, Garcia KC. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 2012, 484:529-33.\",\"year\":2012,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/22446627\",\"text\":\"Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'.\"}},{\"title\":\"Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.\",\"citation\":\"Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, Ozkan E, Leonard WJ, Garcia KC. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nature Immunology 2012, 13:1187-95.\",\"year\":2012,\"link\":{\"url\":\"https://www.ncbi.nlm.nih.gov/pubmed/23104097\",\"text\":\"Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.\"}}],\"clinicalTrials\":[],\"coauthors\":[]},\"patientCareTab\":null,\"newsTab\":{\"searchUrl\":\"/ysm/search/?entityType=Article&profilePageName=aaron_ring\",\"news\":[{\"id\":\"27293\",\"bylineDate\":\"2020-09-11T04:00:00-04:00\",\"title\":\"A New Hope for IL-18 Therapy\",\"summary\":\".\\nCytokine therapies for cancer largely have not lived up to their preclinical promise, due to limited efficacy as well as toxicity. Now, an engineered version of the cytokine IL-18 has shown antitumor efficacy and low toxicity in mouse models. 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The work was published in Nature.\",\"thumbnail\":{\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/b56e2a46-6bc2-4c48-aed0-3d18cbdad396\",\"altText\":null,\"width\":920,\"height\":690,\"imageVariants\":[{\"dimension\":\"Square\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/2fa4baca-e2db-4183-bf9b-9f7d4d89cc3e\",\"width\":690,\"height\":690},{\"dimension\":\"Rectangle\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/4b122edf-1319-4976-9b64-1bbe9d90df36\",\"width\":920,\"height\":494}]},\"url\":\"https://www.cancertherapyadvisor.com/home/cancer-topics/general-oncology/il18-cancer-treatment-cytokine-therapy/\",\"isFeatured\":false,\"source\":\"Cancer Therapy Advisor\"},{\"id\":\"26135\",\"bylineDate\":\"2020-08-26T04:00:00-04:00\",\"title\":\"Sex Differences in COVID-19 Immune Responses Affect Patient Outcomes\",\"summary\":\"Investigators funded by Women’s Health Research at Yale have identified significant differences in how the immune systems of women and men respond to the virus that causes COVID-19.\",\"thumbnail\":{\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/2dfcfaa0-cdda-4ea6-8bbb-03a22ed1d50e\",\"altText\":null,\"width\":1920,\"height\":1080,\"imageVariants\":[{\"dimension\":\"Square\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/cf47fb82-efcb-4262-84e1-66ae60ee41b3\",\"width\":1080,\"height\":1080},{\"dimension\":\"Rectangle\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/02d4d491-8a91-4dfe-bef8-185c4bdf7a12\",\"width\":1920,\"height\":1030}]},\"url\":\"/ysm/news-article/26135/\",\"isFeatured\":false,\"source\":null},{\"id\":\"26887\",\"bylineDate\":\"2020-08-25T04:00:00-04:00\",\"title\":\"Three members in the Department of Immunobiology have received awards from ICIS, the International Cytokine and Interferon Society\",\"summary\":\"Department of Immunobiology members, Carrie Lucas, Aaron Ring and Autumn York, have been announced as ICIS 2020 ICIS Young Investigator Award Winners\",\"thumbnail\":{\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/22a9d246-e8e2-48c9-ab9d-559074778c68\",\"altText\":null,\"width\":2667,\"height\":1500,\"imageVariants\":[{\"dimension\":\"Square\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/8e2a5e3f-f920-4c0d-9107-e5c62f43ef75\",\"width\":1500,\"height\":1500},{\"dimension\":\"Rectangle\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/5281859e-3603-4d45-b116-e80f37629ae1\",\"width\":2667,\"height\":1432}]},\"url\":\"/ysm/news-article/26887/\",\"isFeatured\":false,\"source\":null},{\"id\":\"25582\",\"bylineDate\":\"2020-06-24T15:00:00-04:00\",\"title\":\"Blocking a ‘Jamming Signal’ Can Unleash Immune System to Fight Tumors\",\"summary\":\"Yale researchers have discovered a “jamming signal” that blocks a powerful immune system stimulant called interleukin-18 (IL-18) from reaching tumors, including in cancers that are resistant to conventional immunotherapy treatments, they report June 24 in the journal Nature.\",\"thumbnail\":{\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/1f257497-91c7-49c7-88f1-3abb332e76ce\",\"altText\":null,\"width\":1498,\"height\":871,\"imageVariants\":[{\"dimension\":\"Square\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/a8a18171-6b46-4cff-81b6-ffc50e60daa3\",\"width\":870,\"height\":870},{\"dimension\":\"Rectangle\",\"url\":\"https://ysm-res.cloudinary.com/image/upload/v1/yms/prod/efc1a8ea-5307-4006-bc81-405afa7cb827\",\"width\":1498,\"height\":804}]},\"url\":\"/ysm/news-article/25582/\",\"isFeatured\":false,\"source\":null},{\"id\":\"25489\",\"bylineDate\":\"2020-06-19T16:55:16-04:00\",\"title\":\"Yale Research Presented at 2020 AACR Virtual Annual Meeting II\",\"summary\":\"Yale Cancer Center (YCC) and Smilow Cancer Hospital (SCH) scientists and clinicians are presenting research studies at the 2020 Annual Virtual Meeting II of the American Association for Cancer Research (AACR) June 22 – 24. This program is the second of two virtual annual AACR meetings for this year. 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