{"678252":{"#nid":"678252","#data":{"type":"news","title":"How Physical Force Affects Cancer Treatment","body":[{"value":"\u003Cp\u003EProgrammed Cell Death-1, or PD-1, has become a headline-grabbing molecule best known for its role in cancer immunotherapies called checkpoint inhibitors.\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2\u0022\u003EA study from Georgia Tech and Emory University\u003C\/a\u003E researchers is offering improved understanding of why these inhibitors work \u2014 and how to make them effectively fight cancer for more patients.\u003C\/p\u003E\u003Cp\u003EIn a normal, healthy body, PD-1 is a receptor protein that serves as an important off-switch, or checkpoint. Found on a cell\u2019s surface, it binds with a ligand \u2014 either PD-L1 or PD-L2 \u2014 on another cell surface. This interaction signals the immune systems\u2019 T cells not to attack healthy cells. But sometimes, invading cancer cells also carry a ligand that will bind with PD-1, fooling the body\u2019s immune system into calling off the attack when T cells are needed most.\u003C\/p\u003E\u003Cp\u003EPD-1 blockade therapy is a checkpoint inhibitor that blocks this signaling process, unleashing the full fury of T cells. Still, only 20% to 40% of patients receive clear benefits from this kind of immunotherapy.\u0026nbsp;\u003C\/p\u003E\u003Cp\u003EHere\u2019s the thing: Part of what remains unclear is how PD-1 initiates the stand-down order to T cells. Sometimes, ligands bind with PD-1 and \u003Cem\u003Edon\u2019t\u003C\/em\u003E suppress T cell activity. So, solving the mystery of what else causes PD-1 to work as a checkpoint can open the door to more effective cancer therapies.\u003C\/p\u003E\u003Cp\u003EWallace H. Coulter Department of Biomedical Engineering researcher \u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/faculty\/Cheng-Zhu\u0022\u003ECheng Zhu\u003C\/a\u003E and his collaborators may have found a key: physical force.\u003C\/p\u003E\u003Cp\u003E\u201cMechanical forces are an important but previously overlooked component of immunology in general, and specifically in PD-1 activity,\u201d said Zhu, professor Regents\u0027 Professor and J. Erskine Love Jr. Chair. \u201cThey play a critical role in regulating immune responses.\u201d\u003C\/p\u003E\u003Cp\u003EZhu and his team presented their research in \u003Cem\u003ENature Communications\u003C\/em\u003E, demonstrating that PD-1 is not activated just through interacting or binding with ligands. These ligands must also be anchored to a surface, like a cell membrane, which enables T cells to exert small but measurable forces.\u003C\/p\u003E\u003Cp\u003E\u201cWe show that T cells exert force on this interaction between PD-1 and the ligand. Without that reactive force on the cancer cell ligand, PD-1 doesn\u2019t function,\u201d Zhu said.\u003C\/p\u003E\u003Cp\u003EAnd that means T cells can be fully armed and ready for the fight.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMeasuring the Force\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EThe recent study is a sequel to research \u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/news\/zhu-lab-explains-inhibitory-role-worlds-most-famous-molecule-0\u0022\u003EZhu\u2019s team published in 2021\u003C\/a\u003E that explained PD-1\u2019s suppressive role and its value in immunotherapy. This time, the researchers went deeper, identifying and measuring the physical force involved in PD-1\u2019s function.\u003C\/p\u003E\u003Cp\u003EThey used special tools called molecular tension probes and biomembrane force probes to evaluate the tiny physical force exerted by T cells and understand the connection between this molecular jostling and PD-1 activity.\u0026nbsp;\u003C\/p\u003E\u003Cp\u003EOn a solid cell membrane with the appropriate ligand (PD-L1 for example), T cells exert a force of 4.7 to 12 piconewtons. When the force applied was less than 7 piconewtons, the bond between PD-1 and the ligand got stronger and lasted longer. When the force was higher than 8, the bond weakened and broke more easily.\u003C\/p\u003E\u003Cp\u003E\u201cIf the force is too high, the bond breaks, and that weakens PD-1\u2019s ability to stop T cells,\u201d Zhu explained. \u201cIt\u2019s a molecular balancing act, and the right amount of physical force makes all the difference.\u201d\u003C\/p\u003E\u003Cp\u003EWhile they confirmed that T cells exert small forces on PD-1 attached to a surface-bound ligand, they also discovered that soluble PD-L1 ligands floating freely in the bloodstream lack the mechanical support needed to activate PD-1.\u003C\/p\u003E\u003Cp\u003E\u201cThis explains why soluble ligands don\u2019t trigger T cell inhibition in the same way,\u201d Zhu said.\u003C\/p\u003E\u003Cp\u003EUltimately, the research showed that immune cells need physical as well as chemical cues to properly manage PD-1 activity, and even the tiniest show of force could play a role in our body\u2019s ability to protect itself, against cancer and potentially other diseases.\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u201cNext, we would like to test our in vitro findings in an in vivo setting, using animal models,\u201d Zhu said.\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION:\u003C\/strong\u003E \u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Kaitao-Li-Aff1-Aff2-Aff7\u0022\u003EKaitao Li\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Paul-Cardenas_Lizana-Aff1-Aff2-Aff8\u0022\u003EPaul Cardenas-Lizana\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Jintian-Lyu-Aff1-Aff2-Aff9\u0022\u003EJintian Lyu\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Anna_V_-Kellner-Aff1-Aff10\u0022\u003EAnna V. Kellner\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Menglan-Li-Aff1-Aff2\u0022\u003EMenglan Li\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Peiwen-Cong-Aff1-Aff2\u0022\u003EPeiwen Cong\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Valencia_E_-Watson-Aff1-Aff2\u0022\u003EValencia E. Watson\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Zhou-Yuan-Aff1-Aff2-Aff3-Aff11\u0022\u003EZhou Yuan\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Eunseon-Ahn-Aff4-Aff5-Aff12\u0022\u003EEunseon Ahn\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Larissa-Doudy-Aff1-Aff2\u0022\u003ELarissa Doudy\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Zhenhai-Li-Aff1-Aff3-Aff13\u0022\u003EZhenhai Li\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Khalid-Salaita-Aff1-Aff6\u0022\u003EKhalid Salaita\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Rafi-Ahmed-Aff4-Aff5\u0022\u003ERafi Ahmed\u003C\/a\u003E,\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41467-024-52565-2#auth-Cheng-Zhu-Aff1-Aff2-Aff3\u0022\u003ECheng Zhu\u003C\/a\u003E. \u201cMechanical force regulates ligand binding and function of PD-1.\u201d \u003Cem\u003ENature Communications\u003C\/em\u003E. doi.org\/10.1038\/s41467-024-52565-2\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EFUNDING:\u003C\/strong\u003E This research was supported by the National Science Foundation, grant No. MCA08X014, and the National Institutes of Health, grant Nos. R01CA243486, U01CA250040, U01CA250040S2, RM1GM145394, and F31CA243502. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of any funding agency.\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E","summary":"","format":"limited_html"}],"field_subtitle":[{"value":"Cheng Zhu and collaborators probe the underlying mechanisms of PD-1 checkpoint inhibitor therapy"}],"field_summary":[{"value":"\u003Cp\u003ECheng Zhu and collaborators probe the underlying mechanisms of PD-1 checkpoint inhibitor therapy and discover the critical role of physical force at the molecular level.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Cheng Zhu and collaborators probe the underlying mechanisms of PD-1 checkpoint inhibitor therapy and discover the critical role of physical force."}],"uid":"28153","created_gmt":"2024-11-07 15:56:19","changed_gmt":"2024-11-08 15:32:26","author":"Jerry Grillo","boilerplate_text":"","field_publication":"","field_article_url":"","location":"Atlanta, GA","dateline":{"date":"2024-11-07T00:00:00-05:00","iso_date":"2024-11-07T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"675541":{"id":"675541","type":"image","title":"Zhu lab","body":"\u003Cp\u003ECheng Zhu\u0027s research team studied how mechanical force plays a critical role in the body\u0027s immune system. \u0026nbsp; \u2014 Photo by Jerry Grillo\u003C\/p\u003E","created":"1730993470","gmt_created":"2024-11-07 15:31:10","changed":"1730994774","gmt_changed":"2024-11-07 15:52:54","alt":"Cheng Zhu lab","file":{"fid":"259177","name":"Cheng Zhu lab.jpg","image_path":"\/sites\/default\/files\/2024\/11\/07\/Cheng%20Zhu%20lab.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/2024\/11\/07\/Cheng%20Zhu%20lab.jpg","mime":"image\/jpeg","size":3148396,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/2024\/11\/07\/Cheng%20Zhu%20lab.jpg?itok=z1Zs4JCB"}}},"media_ids":["675541"],"groups":[{"id":"1292","name":"Parker H. Petit Institute for Bioengineering and Bioscience (IBB)"}],"categories":[{"id":"138","name":"Biotechnology, Health, Bioengineering, Genetics"},{"id":"145","name":"Engineering"},{"id":"146","name":"Life Sciences and Biology"}],"keywords":[{"id":"187423","name":"go-bio"},{"id":"187886","name":"PD-1"},{"id":"181927","name":"BME cancer"},{"id":"2470","name":"cancer therapy"},{"id":"187887","name":"checkpoint inhibitor"},{"id":"194075","name":"programmed cell death"},{"id":"1613","name":"Biomedical Engieering"},{"id":"108031","name":"College of Engineering; Coulter Department of Biomedical Engineering"}],"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\u003E\u003Ca href=\u0022mailto:Jerry.grillo@ibb.gatech.edu\u0022\u003EJerry Grillo\u003C\/a\u003E\u003C\/p\u003E","format":"limited_html"}],"email":["Jerry.grillo@ibb.gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}