Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover potential new target for cancer immunotherapy

26.05.2014

Peptide antibodies hit immune-response-stifling MDSCs without harming other vital cells

Scientists have found a way to target elusive cells that suppress immune response, depleting them with peptides that spare other important cells and shrink tumors in preclinical experiments, according to a paper published online by Nature Medicine.

"We've known about these cells blocking immune response for a decade, but haven't been able to shut them down for lack of an identified target," said the paper's senior author, Larry Kwak, M.D., Ph.D., chair of Lymphoma/Myeloma and director of the Center for Cancer Immunology Research at The University of Texas MD Anderson Cancer Center.

The cells, called myeloid-derived suppressor cells (MDSCs), are found abundantly in the microenvironment around tumors. Created with other blood cells in the bone marrow, they interfere with activation and proliferation of T cells, the immune system's attack cells. MDSCs have been shown in mouse models to accelerate cancer progression and metastasis.

"This is the first demonstration of a molecule on these cells that allows us to make an antibody, in this case a peptide, to bind to them and get rid of them," Kwak said. "It's a brand new immunotherapy target."

Kwak has developed anti-cancer therapeutic vaccines to spark an immune system attack against tumors, but their effectiveness has been hindered by factors such as MDSCs that stifle immune response. "The key to taking cancer vaccines to another level is combining them with immunotherapies that target the tumor microenvironment," Kwak said.

Antibodies only bind to target cells

Peptide antibodies developed by Kwak and co-discoverer, Hong Qin, Ph.D., assistant professor of Lymphoma/Myeloma, wipe out MDSCs in the blood, spleen and tumor cells of mice without binding to other white blood cells or dendritic cells involved in immune response.

"That's really exciting because it's so specific for MDSCs that we would expect few, if any, side effects," Kwak said. The team is working to develop the same target for use in humans.

With no candidate targets, the team took an objective approach by applying a peptide phage library to MDSCs, which permitted mass screening for candidate peptides – short sequences of amino acids -- that bind to the surface of the MDSCs.

Peptide phage gathered from the MDSCs were expanded, enriched and then sequenced to identify predominant peptides. The team found two, labeled G3 and H6, that bound only to MDSCs; other candidates were eliminated because they also tied in to other types of cell.

They fused the two peptides to a portion of mouse immune globulin to generate experimental "peptibodies." Both peptibodies bound to both types of MDSC – monocytic white blood cells, which engulf large foreign bodies or cell debris, and granulocytic white cells loaded with tiny granules.

The researchers treated mice with two types of thymus tumor with each peptibody, a control peptibody and an antibody against Gr-1. The G3 and H6 peptibodies depleted both types of MDSC in the blood and spleens of mice in both tumor models, while the Gr-1 antibody only worked against granulocytic MDSC.

Both peptibodies also wiped out the MDSCs in both types of thymic tumor and in the blood and spleen of mice with lymphoma.

Shrinking tumors, identifying alarmins

To see whether MDSC depletion would impede tumor growth, they treated mice with thymic tumors with the peptides every other day for two weeks. Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with controls or the Gr-1 antibody.

Analysis of surface proteins on the MDSCs identified S100A9 and S100A8 as the likely binding targets for the two peptibodies. They're members of the S100 family of proteins, called alarmins, which are released outside the cell as a danger signal in response to inflammation.

MDSCs' mechanisms for blocking immune response are not well-characterized because they've been hard to study for lack of a targeting method, Kwak said.

Kwak and colleagues are working to extend their findings to human MDSCs.

A new class of drugs called immune checkpoint inhibitors block molecules on T cells that shut down immune response, freeing the immune system to attack tumors. The first of these drugs, ipilimumab (Yervoy®) was approved by federal regulators to treat advanced melanoma. It's the only drug ever to lengthen survival for those patients. Additional immune checkpoint inhibitors are under development.

"Immune checkpoint blockade is great," Kwak said. "There have been dramatic response rates, but those drugs also have side effects. Targeting MDSCs could provide an additional way to unleash the immune system."

###

Co-authors with Kwak and first author Qin are Beatrisa Lerman, Ippei Sakamaki, M.D., Ph.D., Guowei Wei, Ph.D., Soungchul Cha, Ph.D., Sheetal Rao, Jianfei Qian, Ph.D., and Qing Yi, M.D., Ph.D., all of Lymphoma/Melanoma; Yared Hailemichael, Ph.D., and Willem Overwijk, Ph.D., of Melanoma Medical Oncology; Roza Nurieva, Ph.D., of Immunology; and Karen Dwyer, Ph.D., and Johannes Roth, Ph.D., of Stem Cell Transplantation and Cellular Therapy; all are associated with the Center for Cancer Immunology Research.

Lerman is a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

Funding for this research was provided by MD Anderson's Specialized Program in Research Excellence in Lymphoma from the National Cancer Institute of the National Institutes of Health (P50 CA136411).

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute (NCI). For ten of the past 12 years, including 2013, MD Anderson has ranked No. 1 in cancer care in "Best Hospitals," a survey published annually in U.S. News & World Report. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

Get MD Anderson News Via RSS Follow MDAnderson News on Twitter

Scott Merville | Eurek Alert!
Further information:
http://www.mdanderson.org/

Further reports about: Cancer Health Immunology MDSC MDSCs blood immune immunotherapy peptides tumors

More articles from Health and Medicine:

nachricht Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>