Epigenetics of Trained Innate Immunity

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Documenting the epigenetic landscape of human innate immune cells reveals pathways essential for training macrophages.

By Ruth Williams | September 25, 2014

 

WIKIMEDIA, CHRISTOPH BOCK (MAX PLANCK INSTITUTE FOR

INFORMATICS)

Genome-wide epigenetic and transcription analyses of monocytes and macrophages have uncovered two crucial pathways driving macrophage training—a recently discovered form of innate immune memory—according to two studies published in Science today (September 25). Together with a third paper documenting the transcriptional diversity of early immune cell progenitors, the studies present the latest results from the ongoing European BLUEPRINT initiative, which aims to decipher the epigenomes of blood cells during health and disease.

 

“They did a very thorough transcriptomic and epigenomic analysis of these cells and . . . they uncover not just immunologic pathways, which would be expected, but also, interestingly, some metabolic pathways that may be important to the different immunologic phenotypes of these cells,” said Ofer Levy of Boston Children’s Hospital and Harvard Medical School who was not involved in the studies.

 

Monocytes are part of the innate immune system. They circulate in the blood, but also exit to surrounding tissues, differentiate into macrophages, and patrol the body disposing of pathogens and dead cells. Under certain conditions, macrophages can become either tolerant of pathogens or trained to react against additional infections. This training of macrophages is a recently discovered process, and aside from providing a physiological answer for some previously unexplained effects of vaccination, it also challenges the established dogma of innate immunity.

 

In humans, the immune system has two arms: innate and adaptive. The traditional view is that innate immunity is broad-acting and non-specific, while adaptive immunity establishes memories for very specific pathogens, explained Christine Stabell Benn, a professor of global health at the Statens Serum Institute in Copenhagen who also did not participate in the studies. “So, if you give a vaccine against measles you induce protective immunity against measles and nothing else.” But, she added, “what we have seen in our epidemiological studies is that vaccines [also] have non-specific effects.” The Bacille Calmette-Guérin (BCG) vaccine, for example, confers protection against a variety of infections with other microorganisms—and trained macrophages appear to be responsible. The new papers, said Stabell Benn, “are now providing the molecular mechanisms behind these epidemiological observations.”

 

Mihai Netea, a professor of medicine at Radboud University in the Netherlands and an author on two of the papers, has characterized trained macrophages in the dish, in animals and in healthy people, comparing the trained phenotype to tolerant macrophages, naive macrophages (neither trained not tolerant), and monocytes. But to get the bigger picture of what defines these different yet related cells, “I went to the group of Hank [Hendrik] Stunnenberg and asked for his help with the epigenetics,” Netea said. Stunnenberg is a professor of molecular biology at Radboud University, an author on all three papers and the coordinator of the BLUEPRINT consortium.

 

Netea, Stunnenberg, and their colleagues collected monocytes from healthy people and from them derived the three macrophage types—tolerant, trained, and naive. In these four cell types, they then analyzed genome-wide distributions of four epigenetic indicators of gene activity: DNAse hypersensitivity and three different histone modifications—trimethylation of histone H3 at lysine 4, monomethylation of histone H3 at lysine 4, and acetylation of histone H3 at lysine 27. They also analyzed genome-wide transcription and transcription factor binding.

 

Together the analyses pointed to specific genes and pathways that defined the four cell types, as well as the genes’ surrounding regulatory regions. Of particular interest was the discovery that genes associated with signaling via cyclic adenosine monophasphate (cAMP)—a molecule regulating cell metabolism, among other processes—and glycolysis—a pathway that produces energy from glucose—were specifically activated in the trained macrophages.

 

The team went on to show that these two pathways were necessary for developing the trained phenotype. Cultured monocytes in which cAMP signaling or the glycolysis pathway were inhibited exhibited impaired production of training-induced cytokines. Inhibition of cAMP or glycolysis in mice increased susceptibility to secondary infections following trained innate immunity.

 

Both training and tolerance induction in macrophages have a number of clinical implications, explained Netea. For example, too much tolerance can cause immunoparalysis—a life-threatening complication of sepsis, he said. Such patients could be helped, added Stunnenberg, “if we could turn around a paralyzed cell and activate it.” But training “can probably also in some situations be detrimental to the host,” said Stabell Benn, by potentially causing excessive inflammation, for example. Having the epigenomic information about these cells, she added, is therefore important “in the first place, to understand what is going on, and in the second place, because it offers the potential of both down-regulating over-energetic cells but also revitalizing those that have been paralyzed.”

 

L. Chen et al., “Transcriptional diversity during lineage commitment of human blood progenitors,” Science, doi: 10.1126/science.1251033, 2014.

 

S. Cheng et al., “mTOR- and HIF-1a–mediated aerobic glycolysis as metabolic basis for trained immunity,” Science, doi: 10.1126/science.1250684, 2014.

 

S. Saeed et al., “Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity,” Science, doi: 10.1126/science.1251086, 2014.

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vaccination, macrophage, innate immunity, immunology, genetics & genomics, epigenetics and disease/medicine

 

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Targeted Brain Cancer Vaccine

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Mouse study demonstrates the ability of a cancer vaccine targeted against a specific oncogenic mutation to elicit a protective anti-tumor immune response.

By Anna Azvolinsky | June 25, 2014

 

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

A vaccine targeting a mutation found in a subset of tumors, including slow-growing brain malignancies called gliomas, can induce an immune response and prevent tumor progression in mice, according to a study published today (June 25) in Nature. Michael Platten, a neuro-oncologist at the German Cancer Research Center in Heidelberg, Germany, and his colleagues have shown in a mouse model of glioma that this peptide vaccine induces a mutation-specific immune response and can fight pre-existing tumors.

 

“This is a proof-of-principle study,” said Darell Bigner, a cancer researcher and brain tumor expert at Duke University in North Carolina. “The tumor-specific peptides [used in this study] have potential as a tumor vaccine, and should be evaluated in human clinical trials.”

 

The vaccine contains a short peptide sequence of the point mutation in the isocitrate dehydrogenase type 1 (IDH1), which is found in more than 70 percent of gliomas. “We wanted to target a tumor-specific antigen, so a frequently found mutation was an obvious choice,” said Platten.

 

The goal of cancer vaccines is to boost the immune system’s ability to recognize tumors as foreign. But so far, tumor-specific vaccines, which have mostly been tested in advanced cancer patients, have generally not been found to improve survival. Vaccinating against a single tumor-associated mutation has presented researchers with a challenge, as the spectrum of mutations change as a tumor progresses.

 

Still, targeting a so-called driver mutation—one that occurs early in tumor development and is likely to be required to sustain tumor growth—may be a viable approach. The IDH1 mutation is thought to be such a driver: it’s one of the earliest mutations to arise in gliomas, and is found in the vast majority of cells within the same tumor. “In the case of gliomas, this tumor-specific antigen may be sufficient as there is no heterogeneity [within individual tumors], to our knowledge which also made this an attractive immunotherapy target,” said Platten.

 

The researchers vaccinated mice that had a humanized version of the major histocompatibility complex (MHC), a set of cell surface molecules that are necessary to mediate specific immunity against antigens, either pathogens or tumor molecules. Because the MHC system differs between mice and humans, this humanized mouse model is a better first preclinical attempt to evaluate the potential utility of an immunotherapy prior to a first-in-human study. The immune response to the vaccine was restricted to a specific type of T cell response, the CD4-positive T cell and was able to control the IDH1 mutation expressing tumors in the mice.

 

The mice used to test the vaccine developed sarcomas rather than gliomas. “Many questions on whether this vaccine will work the same way on gliomas and other tumors with IDH1 mutations remain,” said Bigner.

 

The researchers also showed that four out of 25 patients with gliomas had innate T cell responses to the IDH1 mutations of their tumors.

 

Based on these results, Platten and colleagues in Germany are now going ahead with a small clinical trial to test the safety and immunogenicity of the vaccine in newly diagnosed IDH1-mutated glioma patients. Patients will receive chemotherapy along with the vaccine. “The tumors we are targeting are rather slow-growing . . . as opposed to very aggressive tumors,” said Platten. “This is an advantage because we have a larger time window of opportunity to induce immunity and the patients are not yet immune-compromised from prior chemotherapies.”

 

“The ultimate goal would be to target gliomas with a combination of active vaccination and a tumor microenvironment-targeted therapy,” said Platten. The vaccine could, in theory, also be effective for other tumor types that harbor the IDH1 mutation.

 

“Cancer vaccination is making a major rebound. There are many exciting trials coming up based on preclinical data,” said Drew Pardoll, an immune-oncology expert at the Johns Hopkins University School of Medicine. “Combining cancer vaccines with the new [immune checkpoint-inhibiting] antibodies is one of several exciting approaches in cancer vaccination right now.”

 

T. Schumacher et al., “A vaccine targeting mutant IDH1 induces anti-tumour immunity,” Nature, doi:10.1038/nature13387, 2014.

Tags

tumor targeting, neuroimmunology, mutation, immunotherapy, glioma, cancer vaccine, cancer and brain cancer

 

 

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