Immune outposts inside tumors predict post-surgery outcomes

The immune system establishes “forward operating bases”, or lymph node-like structures, inside the tumors of some patients with kidney and other urologic Read more

Hedgehog pathway outside cilia (with CBD bonus)

The Hedgehog pathway has roles in both specifying what embryonic cells will become and in guiding growing neural Read more

Tracking how steroid hormone receptor proteins evolved

When thinking about the evolution of female and male, consider that the first steroid receptor proteins, which emerged about 550 million years ago, were responsive to estrogen. The ancestor of other steroid hormone receptors, responsive to hormones such as testosterone, progesterone and cortisol, emerged many millions of years later. Biochemist Eric Ortlund and colleagues have a new paper in Structure that reconstructs how interactions of steroid receptor proteins evolved over time. This is a complex Read more

Emory Vaccine Center

Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity.

Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins such as PD-1 on their surfaces. PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers.

Those drugs are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, Ahmed’s lab found that exhausted cells are not all alike, and the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of “stem-like” cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population, but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, and are unable to migrate to sites of infection and contain lower amounts of proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says postdoctoral fellow Will Hudson, PhD, first author of the Immunity paper. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1 blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer. Read more

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Hope Clinic part of push to optimize HIV vaccine components

Ten years ago, the results of the RV144 trial– conducted in Thailand with the help of the US Army — re-energized the HIV vaccine field, which had been down in the dumps. It was the first vaccine clinical trial to ever demonstrate any efficacy in preventing HIV. The Hope Clinic of Emory Vaccine Center has been involved in efforts to build on the RV144 trial’s promising results. These early-stage studies have been optimizing the best vaccine components and techniques for larger vaccine efficacy trials, some of which are now underway.

Nadine Rouphael, interim director of the Hope Clinic, was first author on a recent paper in Journal of Clinical Investigation, reporting a multi-center study from the HIV Vaccine Trials Network. HVTN is headquartered at the Fred Hutchinson Cancer Research Center in Seattle and supported by the National Institute of Allergy and Infectious Diseases.

“Our study shows that there are tools available to us now to improve on the immunogenicity seen in RV144, which may lead to better efficacy in future field trials,” Rouphael says. (See statement on the HVTN 105 study here.) Read more

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Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

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Leaving out sugar makes a better antibody drug

There’s a bit of sugar attached to your billion-dollar biotech product. Omitting the sugar (fucose) can help the product work better, Emory immunologists think.

Fucosylation is the red triangle on this diagram of the carbohydrate modifications of antibodies. Adapted from KTC Shade + RM Anthony, Antibodies (2013) and used through Creative Commons license.

Many drugs now used to treat cancer and autoimmune diseases are antibodies, originally derived from the immune system. A classic example of a “therapeutic antibody” is rituximab, a treatment for B cell malignancies that was FDA-approved in 1997. It has been responsible for billions of dollars in revenue for its maker, pharmaceutical giant Roche.

Researchers at Emory Vaccine Center previously observed that in a mouse model of chronic viral infection, a traffic jam inside the body limits how effective therapeutic antibodies can be. One of the ways these antibodies work is to grab onto malignant or inflammatory cells. One end of the antibody is supposed to bind the target cell, while another is a flag for other cells to eliminate the target cell. During a chronic viral infection, a mouse’s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from depleting their target cells.

In a recent Science Immunology paper, postdoc Andreas Wieland, Vaccine Center director Rafi Ahmed and colleagues showed that antibodies that lack fucosylation have an enhanced ability to get rid of their intended targets. Fucosylation is a type of sugar modification of the antibody. (It is the red triangle in the diagram, provided by Wieland.) When it is not present, then the “flag for removal” region of the antibody can interact more avidly with the Fc gamma receptor on immune cells. Thus, the introduced antibodies can compete more effectively with the antibodies being produced by the body already.

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Posted on by Quinn Eastman in Immunology 1 Comment

Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

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Four hot projects at Emory in 2017

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

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Update on SIV remission studies

Tab Ansari’s research at Emory/Yerkes on how an antibody treatment can push monkeys infected with SIV into remission was published in Science last year. At that time, Ansari told Lab Land about follow-up experiments to probe which immune cells are needed for this effect, which surprised many HIV/AIDS experts.

Ansari’s partner on the project, NIAID director Anthony Fauci, described the follow-up work in July at the International AIDS Society Conference in Paris. We thank Treatment Action Group’s Richard Jefferys for taking notes and posting a summary:

The approach that the researchers took was to deplete different types of immune cells in the animals controlling SIV viral load, then assess whether this led to an increase in viral replication. The experiments compared:

*Antibodies to the CD8 receptor alpha chain, which deplete CD8 T cells, natural killer T cells (NKTs) and natural killer (NK) cells

*Antibodies to the CD8 receptor beta chain, which deplete CD8 T cells

*Antibodies to CD20, which deplete B cells

According to Fauci’s slides, which are available online, there was a transient rebound in viral load with the CD8 alpha antibody and to a small degree with the CD8 beta. This suggests NKTs and NK cells are making a contribution to the observed control of SIV replication, but a role for CD8 T cells cannot be ruled out.

For comparison, a study from Guido Silvestri and colleagues at Yerkes published in 2016 found that treating SIV-infected monkeys with anti-CD8 antibodies, without stopping antiretroviral drugs, resulted in a rebound in virus levels. [They used ultrasensitive assays to detect the rebound.] However, the Yerkes team only used antibodies to the CD8 receptor alpha chain.

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Flu meeting at Emory next week

We are looking forward to the “Immunology and Evolution of Influenza” symposium next week (Thursday the 25th and Friday the 26th).

The symposium is taking place in Whitehead Auditorium in the Whitehead Biomedical Research Building. Talks from flu researchers based around the country, followed by a poster session, are on Thursday. From Emory, Jacob Kohlmeier and Rafi Ahmed are speaking Friday morning.

Organizers are asking for registration by Friday the 19th. The symposium is jointly sponsored by the Center for Inference and Dynamics of Infectious Diseases, funded by NIGMS, and the Center for Modeling Immunity to Influenza Infection, funded by NIAID.

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Cancer immunotherapy responses in the clinic: T cell revival as predictor

In lung cancer patients who were taking immunotherapy drugs, testing for revived immune cells in their blood partially predicted whether their tumors would shrink. The results were published online by PNAS on April 26.

This finding comes from a small study of 29 patients, who were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, also known as checkpoint inhibitors.

The study supports a straightforward idea: if tumor-specific CD8 T cells appear to respond to the drug (nivolumab, pembrolizumab or atezolizumab), that’s a good sign. This avenue of investigation may also help researchers figure out why some patients do not benefit from checkpoint inhibitor drugs, and how to combine those drugs with other treatments to increase response rates.

While looking for activated immune cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with the treatment or combine it with something else, says co-senior author Suresh Ramalingam, MD, Winship’s deputy director.

“We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue,” says Rafi Ahmed, PhD, director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. “We believe some of the activated T cells in patients’ blood may be on their way to the tumor.”

The rest of the Emory Vaccine Center/Winship Cancer Institute press release is here. A few additional points: Read more

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Zika immunology from returned travelers

At the American Association for the Advancement of Science meeting in Boston last weekend, Emory Vaccine Center researcher Mark Mulligan presented some limited findings on immune responses in Zika-infected humans, who were returned US travelers or expatriates.

The results were intriguing, despite the small number of study participants: five, two of whom were pregnant. Detailed information has not been available about immune responses against Zika in humans, especially T cell responses.

Highlights from Mulligan’s abstract:

*All five seemed to have a hole in their immune systems – functional antiviral “killer” CD8 T cells were rare, despite activation of CD8 T cells in general and strong responses from other cell types.

*Cross-reactive immune responses, based on previous exposure to dengue and/or yellow fever vaccine, may have blunted Zika’s peak.

*”Even with prolonged maternal viremia, both pregnancies resulted in live births of apparently healthy babies.” Read more

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