{"647582":{"#nid":"647582","#data":{"type":"news","title":"Zhu Lab Explains the Inhibitory Role of World\u2019s Most Famous Molecule","body":[{"value":"\u003Cp\u003EA so-called \u0026ldquo;checkpoint\u0026rdquo; protein found on the immune system\u0026rsquo;s all-important T cells called PD-1 might be the most famous molecule on the planet. It was an anti-PD-1 drug, along with radiation therapy, that disintegrated former U.S. President Jimmy Carter\u0026rsquo;s brain tumors in 2015.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EUnder normal conditions, PD-1 serves an important role as an off-switch, preventing well-intentioned T cells from running amok and attacking normal, healthy cells by mistake. It does this by binding with a protein called PD-L1, found on some normal and some cancer cells. This interaction basically signals the T cell to leave the other cell alone. Unfortunately, sometimes the other cell is cancer, which then goes unbothered because PD-1 told the T cell to stand down.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe immunotherapy drug used to treat President Carter, Keytruda, is a checkpoint inhibitor. It inhibited PD-1, freeing the T cells to do their job and destroy the brain tumor. Since then, research into the molecule has expanded and PD-1 blockade continues its evolution as a promising treatment against solid tumors. The Japanese scientist who discovered the protein in 1992, Tasuku Honjo, won the Nobel Prize in 2018.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;It has become a very hot molecule,\u0026rdquo; said \u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/faculty\/Cheng-Zhu\u0022\u003ECheng Zhu\u003C\/a\u003E, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and the George W. Woodruff School of Mechanical Engineering at Tech. \u0026ldquo;But only a minor fraction of cancer patients \u0026mdash; about one third of the melanoma patients who have been treated with the blockade therapy \u0026mdash; are responsive, indicating an incomplete understanding of how PD-1 works.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EZhu and his colleagues are particularly interested in explaining how PD-1 inhibits T-cell activity, and they unravel one part of the mystery in a new paper in \u003Cem\u003ENature Communications\u003C\/em\u003E. Using technology Zhu developed decades ago that measures the biochemistry on live cell membranes, the researchers discovered that PD-1 disrupts the recruitment of CD8, a protein co-receptor that partners in T cell signaling and activation.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;The results of our study identify a PD-1 inhibitory mechanism that disrupts cooperative molecular interactions and prevents CD8 from augmenting antigen recognition,\u0026rdquo; Zhu said. \u0026ldquo;This explains the molecule\u0026rsquo;s potent inhibitory function regarding T cell activation and also explains its value as a target for clinical intervention.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe lead author on the paper is Kaitao Li, a research scientist in Zhu\u0026rsquo;s \u003Ca href=\u0022https:\/\/zhu-lab-website.appspot.com\/\u0022\u003ECellular and Molecular Biomechanics Lab\u003C\/a\u003E, who focused on PD-1 for his Ph.D. dissertation in 2016. Li\u0026rsquo;s interest in the molecule has only grown through his friendship with \u003Ca href=\u0022https:\/\/vaccines.emory.edu\/faculty-evc\/primary-faculty\/ahmed_rafi.html\u0022\u003ERafi Ahmed\u0026rsquo;s\u003C\/a\u003E lab at Emory. Ahmed is a co-author of the new \u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-021-22965-9\u0022\u003E\u003Cem\u003ENature Communications\u003C\/em\u003E paper.\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;I was taking an immunology class at Emory in 2010, and it was the first time I came across the PD-1 molecule,\u0026rdquo; Li recalled. \u0026ldquo;A friend of mine was a grad student in Rafi\u0026rsquo;s lab, and eventually, I became very inspired by their work.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAhmed\u0026rsquo;s lab identified PD-1 as a major mediator of T cell dysfunction during chronic infection, work that ultimately translated into human clinical studies of blockade therapy. Meanwhile, the Zhu lab had been focusing mainly on the basic science of on T cell activation and T cell receptors \u0026ndash; TCR, a protein complex used by T cells for recognizing invading antigens.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;What excites me most is that [this study] reinforces and extends the work that Dr. Zhu did 10 years ago on the sequence of events leading up to T cell activation, but now it brings PD-1 into the story, revealing how PD-1 dampens T cell activation,\u0026rdquo; explained Simon Davis, paper co-author, whose immunology lab at the University of Oxford has studied PD-1 and other proteins for about 20 years. \u0026ldquo;We had proposed a long time ago that the activation sequence is dictated by the relative strengths of protein interactions involves, but Dr. Zhu\u0026rsquo;s lab was able to tease all this apart.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EWhile Zhu\u0026rsquo;s lab is rich in basic science, there is a translational aspect to this work. A biotech company that spun out Davis\u0026rsquo; work is interested in Zhu\u0026rsquo;s discoveries, particularly the series of interactions among all of these critical molecules engaged in the immune response, Davis said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAnd it\u0026rsquo;s bound to get more interesting going forward. Zhu and Li, who collaborated on PD-1 research for a paper in 2017, said they are planning two more studies focusing on the notable molecule, now the target of a hopeful treatment regimen that still has plenty of room for improvement.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;There has certainly been some clinical success even though we don\u0026rsquo;t fully understand the mechanism behind it,\u0026rdquo; Zhu said. \u0026ldquo;But there is still a long way to go because two thirds of the patients are not responding successfully. Why? We have another study planned to try to answer that question.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cem\u003EThis research was supported by National Institutes of Health grants \u003C\/em\u003E\u003Cem\u003EU01CA214354, R01CA243486, and U01CA250040 (to C.Z. and R.A.).\u003C\/em\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003ECITATIONS: Kaitao Li, Zhou Yuan, Jintian Lyu, Eunseon Ahn, Simon J. Davis, Rafi Ahmet, Cheng Zhu, \u0026ldquo;\u003C\/strong\u003EPD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition\u0026rdquo; (\u003Cem\u003ENature Communications\u003C\/em\u003E, May 2021)\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003ERelated Links:\u003C\/strong\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003E\u0026ldquo;\u003C\/strong\u003E\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-021-22965-9\u0022\u003EPD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition\u0026rdquo; (\u003Cem\u003ENature Communications\u003C\/em\u003E, May 2021)\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Ca href=\u0022https:\/\/zhu-lab-website.appspot.com\/\u0022\u003ECellular and Molecular Biomechanics Laboratory\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Ca href=\u0022https:\/\/www.cancerresearch.org\/join-the-cause\/cancer-immunotherapy-month\/30-facts\/20\u0022\u003EJimmy Carter\u0026rsquo;s Cancer Immunotherapy Story\u003C\/a\u003E\u003C\/p\u003E\r\n","summary":null,"format":"limited_html"}],"field_subtitle":[{"value":"New research teases apart the mechanisms behind the checkpoint protein PD-1"}],"field_summary":[{"value":"\u003Cp\u003ENew research teases apart the mechanisms behind the checkpoint protein PD-1\u003C\/p\u003E\r\n","format":"limited_html"}],"field_summary_sentence":[{"value":"New research teases apart the mechanisms behind the checkpoint protein PD-1"}],"uid":"28153","created_gmt":"2021-05-18 21:37:55","changed_gmt":"2021-05-25 15:29:28","author":"Jerry Grillo","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2021-05-18T00:00:00-04:00","iso_date":"2021-05-18T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"647578":{"id":"647578","type":"image","title":"Zhu Lab Tech","body":null,"created":"1621373088","gmt_created":"2021-05-18 21:24:48","changed":"1621373088","gmt_changed":"2021-05-18 21:24:48","alt":"","file":{"fid":"245844","name":"Zhu lab tech.jpg","image_path":"\/sites\/default\/files\/images\/Zhu%20lab%20tech.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/Zhu%20lab%20tech.jpg","mime":"image\/jpeg","size":3236507,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/Zhu%20lab%20tech.jpg?itok=2SWRIlyM"}},"647581":{"id":"647581","type":"image","title":"Cheng and Kaitao","body":null,"created":"1621373514","gmt_created":"2021-05-18 21:31:54","changed":"1621373514","gmt_changed":"2021-05-18 21:31:54","alt":"","file":{"fid":"245845","name":"Cheng and Kaitao.jpg","image_path":"\/sites\/default\/files\/images\/Cheng%20and%20Kaitao.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/Cheng%20and%20Kaitao.jpg","mime":"image\/jpeg","size":932747,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/Cheng%20and%20Kaitao.jpg?itok=NL8E4BN0"}}},"media_ids":["647578","647581"],"groups":[{"id":"1292","name":"Parker H. Petit Institute for Bioengineering and Bioscience (IBB)"},{"id":"1254","name":"Wallace H. Coulter Dept. of Biomedical Engineering"},{"id":"1188","name":"Research Horizons"}],"categories":[],"keywords":[{"id":"1612","name":"BME"},{"id":"187423","name":"go-bio"},{"id":"126571","name":"go-PetitInstitute"},{"id":"187915","name":"go-researchnews"},{"id":"187886","name":"PD-1"},{"id":"187887","name":"checkpoint inhibitor"},{"id":"8084","name":"Cancer treatment"},{"id":"385","name":"cancer"},{"id":"4514","name":"immunotherapy"},{"id":"1895","name":"Immunology"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[{"id":"71891","name":"Health and Medicine"}],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EWriter: \u003Ca href=\u0022mailto:jerry.grillo@ibb.gatech.edu\u0022\u003EJerry Grillo\u003C\/a\u003E\u003C\/p\u003E\r\n","format":"limited_html"}],"email":["Jerry.grillo@ibb.gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}