{"id":135946,"date":"2018-04-02T08:00:49","date_gmt":"2018-04-02T12:00:49","guid":{"rendered":"https:\/\/today.uconn.edu\/?p=135946"},"modified":"2018-04-10T10:47:59","modified_gmt":"2018-04-10T14:47:59","slug":"new-compound-helps-activate-cancer-fighting-t-cells","status":"publish","type":"post","link":"https:\/\/today.uconn.edu\/2018\/04\/new-compound-helps-activate-cancer-fighting-t-cells\/","title":{"rendered":"New Compound Helps Activate Cancer-Fighting T Cells"},"content":{"rendered":"
\"Researchers<\/a>
Researchers Amy Howell and Jos\u00e9 Gasc\u00f3n of the chemistry department discuss a molecular simulation on a laptop monitor in the academic wing of the Chemistry Building. (Sean Flynn\/UConn Photo)<\/figcaption><\/figure>\n

Invariant natural killer T (i<\/em>NKT) cells are powerful weapons our body\u2019s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.<\/p>\n

While several chemical compounds have shown promise stimulating i<\/em>NKT cells in mice, their ability to activate human i<\/em>NKT cells has been limited.<\/p>\n

Now, an international team of top immunologists, molecular biologists, and chemists led by University of Connecticut chemistry professor Amy Howell reports<\/a>\u00a0in\u00a0Cell Chemical Biology\u00a0<\/em>the creation of a new compound that appears to have the properties researchers have been looking for.<\/p>\n

The compound \u2013 a modified version of an earlier synthesized ligand \u2013 is highly effective in activating human i<\/em>NKT cells. It is also selective \u2013 encouraging i<\/em>NKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumor immunity.<\/p>\n

One of the limitations of earlier compounds was their tendency to cause i<\/em>NKT cells to release a rush of different cytokines. Some of the cytokines turned the body\u2019s immune response on, while others turned it off. The conflicting cytokine activity hampered the compounds\u2019 effectiveness.<\/p>\n

The new compound\u00a0\u2013 called AH10-7 \u2013 is uniquely structured so that does not happen.<\/p>\n

\u201cOne of the goals in this field has been to identify compounds that elicit a more biased or selective response from i<\/em>NKT cells, and we were able to incorporate features in AH10-7 that did that,\u201d says Howell, who has been studying the role of glycolipids in modulating the human immune system for more than 20 years.<\/p>\n

The robust study, years in the making, also applied advanced structural and 3-D computer modeling analysis to identify the underlying basis for the new compound\u2019s success. These highly detailed insights into what is happening at the molecular level open up new paths for research and could lead to the development of even more effective compounds.<\/p>\n

\u201cWe synthesized a new compound, demonstrated its effectiveness with biological data, and learned more about its interactions with proteins through X-ray crystallography and computational analysis,\u2019\u2019 says UConn associate professor of chemistry Jos\u00e9 Gasc\u00f3n, a specialist in quantum and molecular mechanics. \u201cWe are providing protocols so that other scientists can rationally design related molecules that elicit desired responses from i<\/em>NKT cells.\u201d<\/p>\n

The molecular analysis helped validate and explain experimental results.<\/p>\n

“By exposing a crystalized form of the molecular complex to a high-intensity X-ray beam at the Australian Synchrotron, we were able to obtain a detailed 3-D image of the molecular interplay between the invariant natural killer T cell receptor and AH10-7,\u201d says corresponding author J\u00e9r\u00f4me Le Nours, a structural biologist with the Biomedicine Discovery Institute at Monash University in Australia. \u201cThis enabled us to identify the structural factors responsible for AH10-7\u2019s potency in activating\u00a0i<\/em>NKT cells. This valuable insight could lead to the development of even more effective anti-metastatic ligands.\u201d<\/p>\n

Efforts to harness the therapeutic potential of human i<\/em>NKT cells began 20 years ago with the discovery that natural and synthetic forms of glycolipid ligands known as alpha-galactosylceramides, or \u03b1-GalCers for short, were potent activators of i<\/em>NKT cells. Scientists immediately recognized their possible value in fighting cancer and other diseases. These \u03b1-GalCer ligands serve as tiny dock masters in our immune system, helping antigen-presenting cells attract and bind with i<\/em>NKT cells so they can be activated to kill cancerous cells or fight off pathogens and other foreign invaders.<\/p>\n

\"Comparison<\/a>
Comparison of tumor suppression in the lungs of wild mice (top row) and ‘humanized’ mice (bottom row). First column represents untreated mice. Second column, mice treated with the KRN7000 synthesized compound. Third column, mice treated with the new compound AH10-7. Results show the newly synthesized compound AH10-7 is at least as effective as KRN7000 in suppressing growth of melanoma cells. (Images courtesy of Dr. Steven Porcelli and Weiming Yuan)<\/figcaption><\/figure>\n

The first promising version of a synthesized \u03b1-GalCer was a compound known as KRN7000. While KRN7000 powerfully stimulated i<\/em>NKT cells in both mice and humans, it triggered the release of a flood of many types of cytokines, limiting its potential for clinical applications. Since then, researchers have been searching for new variations of KRN7000 that maintain their effectiveness in activating human i<\/em>NKT cells while also favoring release of the powerful tumor fighting Th1 cytokines.<\/p>\n

In the current study, Howell and colleagues made two significant modifications to an \u03b1-GalCer ligand in an attempt to make it more effective. They found that adding a hydrocinnamoyl ester on to the sugar stabilized the ligand and kept it close to the surface of the antigen-presenting cell, thereby enhancing its ability to dock with and stimulate human i<\/em>NKT cells. In addition, trimming off part of the molecule\u2019s sphingoid base appears to initiate the critical Th1 cytokine bias. Both changes, working in tandem, strengthened the effectiveness of the entire molecular complex in terms of activating human i<\/em>NKT cells, Howell says.<\/p>\n

To further validate AH10-7\u2019s effectiveness, the researchers tested the new compound in wild mice as well as partially \u201chumanized\u201d mice, whose genomes were modified to mimic the human i<\/em>NKT cell response. Notably, AH10-7 was shown to be at least as effective as KRN7000 in suppressing the growth of melanoma cells in the partially humanized mice.<\/p>\n

Dr. Steven Porcelli, an immunologist with the Albert Einstein College of Medicine in N.Y., also served as a corresponding author on the study.<\/em><\/p>\n

The research was supported in part by NIH grants U01 GM111849, R01 GM087136, R01 AI45889, and R01 AI 091987.<\/em><\/p>\n

A complete list of the contributing researchers and funding resources for the study \u201cDual Modifications of \u03b1-Galatosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity\u201d can be found here<\/a>.<\/em><\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

UConn researchers have identified mechanisms responsible for improved immune system activity, offering new approaches for more effective cancer treatments and vaccines.<\/p>\n","protected":false},"author":12,"featured_media":135800,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_crdt_document":"","wds_primary_category":0,"wds_primary_series":0,"wds_primary_attribution":0,"footnotes":""},"categories":[2230,2226,2231,2076,2225],"tags":[],"magazine-issues":[],"coauthors":[1928],"class_list":["post-135946","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-cancer","category-clas","category-health-well-being","category-research","category-uconn-storrs"],"pp_statuses_selecting_workflow":false,"pp_workflow_action":"current","pp_status_selection":"publish","acf":[],"publishpress_future_action":{"enabled":false,"date":"2026-04-25 23:24:44","action":"change-status","newStatus":"draft","terms":[],"taxonomy":"category","extraData":[]},"publishpress_future_workflow_manual_trigger":{"enabledWorkflows":[]},"_links":{"self":[{"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/posts\/135946","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/users\/12"}],"replies":[{"embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/comments?post=135946"}],"version-history":[{"count":12,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/posts\/135946\/revisions"}],"predecessor-version":[{"id":136411,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/posts\/135946\/revisions\/136411"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/media\/135800"}],"wp:attachment":[{"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/media?parent=135946"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/categories?post=135946"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/tags?post=135946"},{"taxonomy":"magazine-issue","embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/magazine-issues?post=135946"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/today.uconn.edu\/wp-rest\/wp\/v2\/coauthors?post=135946"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}