When The Scientist first spoke with Howard Hang almost 20 years ago, the chemical microbiologist had just started up his own lab at The Rockefeller University with the goal of applying his expertise in organic chemistry to understand how respiratory pathogens cause disease. "We want to keep pushing the limits of what we can do with chemistry,” he said, “to study how viruses and bacteria perturb host cells."
Up to that point, Hang’s career illustrated how chemical tools could be leveraged to study biochemical pathways in cells and how pathogens disrupt them.1,2 The Scientist reached out to Hang again to see how his work has progressed after almost two decades. Since then, Hang has shifted his focus from studying the microbes that cause disease to exploring those that improve a host’s tolerance to infections and response to immunotherapies. His team has not only described bacterial species that mediate these effects, but also the mechanisms behind them.
Commensal Bacteria: Allies Against Infections
Around ten years ago, the emergence of the microbiome as an important modulator of host health led Hang to wonder which beneficial bacteria in the gut microbiota could help fight pathogens and how they do so.
To explore this question, his team developed a simple screening system using the worm Caenorhabditis elegans. “[C. elegans] was a very inexpensive system to set up and do some exploratory studies, purely out of curiosity,” he said. “We didn't have a particular disease in mind, and when we failed, it wasn't a huge disaster.”
By exposing the transparent nematodes to the commensal gut bacterium Enterococcus faecium and then challenging the worms with a pathogenic Salmonella strain, they showed that E. faecium enhanced the worm’s tolerance to the pathogen through the actions of the secreted antigen A (SagA) enzyme. This enzyme breaks down the bacterial cell wall into smaller products that the immune system can detect more easily.3 “To our surprise, even though the beneficial bacteria did prevent the infection [in] C. elegans, it wasn't doing it directly on the pathogen, but it was modulating the host immune response instead,” Hang explained.
The commensal bacteria Enterococcus faecium (green) acts as a host’s ally by secreting factors that increase its tolerance against gut infections and enhance its response to immunotherapies.
Chongwang Wu, Hang’s laboratory
The researchers then demonstrated that they could extend these effects to other animal models and pathogens, reinforcing the idea that specific factors from commensal bacteria shield a host from gut infections by improving its intestinal barrier defenses.4
While Hang and his team were exploring the protective effects of commensal bacteria against intestinal infections, a set of studies published in 2018 revealed another beneficial effect that E. faecium and its factors could provide to their hosts: Improving the response to immunotherapies.5-7
Microbiota Modulators of Cancer Treatment Response
According to Hang, finding out that the bacteria his team was studying played a role in cancer therapies was another unexpected turn in his career. A set of papers published in the late 2010s showed that cancer patients who respond better to immunotherapies have a different microbiome composition than patients who do not, suggesting that the gut microbes modulate the efficacy of those treatments.5-7
“When I looked at those papers, I noticed that the bacteria that we had studied were enriched in the immunotherapy-responsive patients. At that time, nobody had studied the role of that specific bacterial species in cancer immunotherapy,” Hang said.
Since Hang’s team had demonstrated that E. faecium and SagA could enhance a host’s immune response during infection, the team wondered if the same would happen to the immune response during cancer treatment.
Using a mouse tumor model, the researchers showed that the presence of E. faecium, as well as the expression of SagA in non-protective bacteria, improved immunotherapy efficacy.8 Hang’s team also described that these anti-tumor effects required the activation of the nucleotide-binding oligomerization domain-containing protein 2 (NOD2). This protein is a pattern recognition receptor found on some immune cells that detects bacterial conserved motifs and elicits antimicrobial responses.9,10
“The stimulation of those cells, which survey multiple tissues, provides a very simple explanation for when those cells are activated by unique bacteria like Enterococcus. It not only promotes gut immunity, but also promotes immunity at other sites,” Hang explained.
A Complete Cycle: Taking Basic Science to Humans
The discoveries of the beneficial effects of E. faecium and SagA have prompted Hang to look beyond animal models. One avenue his team is currently exploring is assessing whether Enterococcus species in general from cancer patients, which often exhibit antibiotic resistance, would have the same effects on the immune response.
Additionally, the researchers are exploring other commensal bacteria and probiotic strains to see if they could also have beneficial effects on the host. This is particularly important as Enterococcus bacteria are often drug-resistant and potentially pathogenic, what limits their use in humans, Hang explained.
Following the identification of SagA as the Enterococcus factor that boosts the effects of immunotherapies, Hang’s lab is currently collaborating with a biotechnology company to express the SagA gene in a probiotic bacterial species and assess how the bacteria affects cancer immunotherapy response in patients with renal cell carcinoma—a study that has recently been approved by the FDA to proceed to a Phase 1 clinical trial.
“[This] story is quite remarkable. If I look back, we started in a very curiosity, exploratory study in C. elegans, and for that to come all the way into mouse models and now into humans is, I would say, completely unexpected,” Hang said.
- Hang HC, et al. A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation. Proc Natl Acad Sci U S A. 2003;100(25):14846-14851.
- Maehr R, et al. Asparagine endopeptidase is not essential for class II MHC antigen presentation but is required for processing of cathepsin L in mice. J Immunol. 2005;174(11):7066-7074.
- Rangan KJ, et al. A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science. 2016;353(6306):1434-1437.
- Pedicord VA, et al. Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Sci Immunol. 2016;1(3):eaai7732.
- Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97-103.
- Matson V, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104-108.
- Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
- Griffin ME, et al. Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy. Science. 2021;373(6558):1040-1046.
- Caruso R, et al. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity. 2014;41(6):898-908.
- Griffin ME, et al. N-Arylpyrazole NOD2 Agonists Promote Immune Checkpoint Inhibitor Therapy. ACS Chem Biol. 2023;18(6):1368-1377.
