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!
Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
18.07.2018 | Materials Sciences
18.07.2018 | Life Sciences
18.07.2018 | Health and Medicine