Discovery could lead to new treatments for cancer and tumors, but probably not to any new diagnostic assays for clinical laboratories
Researchers at the University of Texas Southwestern (UTSW) Medical Center have reported discovery of “acid walls” that appear to protect various types of cancer tumors from attack by the body’s immune system cells. Though the discovery is not directly related to a biomarker for a clinical laboratory diagnostic test, the basic research will help scientists develop ways to address the tumor’s acid wall strategy for defeating the immune system.
The UT scientists made their discovery using an internally developed imaging technique that employs nanoparticle probes to detect levels of acidity in cells. The research, they suggest, “could pave the way for new cancer treatment approaches that alter the acidic environment around tumors,” according to a UTSW press release.
“This study revealed a previously unrecognized polarized extracellular acidity that is prevalent around cancer cells,” said lead study author Jinming Gao, PhD (above), Professor in the Harold C. Simmons Comprehensive Cancer Center and head of the Gao Lab at UT Southwestern Medical Center, in a press release. Gao believes the study “will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release notes. (Photo copyright: University of Texas.)
Developing Acid Walls
As explained in the press release, scientists have long known that cancer cells are slightly more acidic than most healthy tissue. Gao and his team designed a nanoparticle known as pegsitacianine—a pH-sensitive fluorescent nanoprobe for image-guided cancer surgery—that disassembles and lights up when exposed to the acidic conditions in tumors.
However, “it was unclear why these nanoparticles fluoresced since a tumor’s acidity was thought to be too mild to trigger their activation,” the press release note.
To learn more, they used nanoparticle probes to illuminate a variety of individual cancer cells sampled from humans and mice, including lung, breast, melanoma, and glioblastoma, as well as tumor tissue. They discovered that the cancer cells secreted lactic acid—a waste product of digested glucose—at higher levels than previously known. The cells “pumped” the acid away from their malignant neighbors to form a protective “acid wall” around the tumor, the researchers noted in Nature Biomedical Engineering.
“Samples from human tumors showed that this acid wall was practically devoid of CD8+ T cells within the tumors, an immune cell type known to fight cancer,” the press release states. “When the researchers grew cancer cells and CD8+ T cells together in petri dishes that had been acidified to a 5.3 pH, the cancer cells were spared while the CD8+ T cells perished within three hours, suggesting that this severe acidity might thwart immune cell attack without harming the cancer cells.”
Gao’s team previously discovered that sodium lactate, the “conjugate base of lactic acid” as they describe it, increases the longevity of T cells and thus enhances their cancer-fighting capabilities. The researchers described the two molecules—lactate and lactic acid—as “Dr. Jekyll and Mr. Hyde,” and suggested that future therapies could seek to convert lactic acid to lactate.
“Gao noted that this discovery will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release states.
Commercializing the Technology
Pegsitacianine was designed to aid cancer surgeons by illuminating the edges of solid metastatic tumors in real time during surgery, a 2023 UTSW Medical Center press release explains. About 24 hours prior to surgery, nanoprobes are delivered via IV. Then, the surgeon uses a near-infrared camera to visualize the cells.
UTSW has licensed pegsitacianine to OncoNano Medicine, a Dallas-area biotech startup launched to commercialize technologies from Gao Lab. Gao and his colleague Baran Sumer, MD, Professor and Chief of the Division of Head and Neck Oncology in UT Southwestern Medical Center’s Department of Otolaryngology and co-author on the study, both sit on OncoNano’s advisory board.
In January 2023, OncoNano announced that pegsitacianine had received Breakthrough Therapy Designation for Real-Time Surgical Imaging from the US Food and Drug Administration (FDA), which will fast-track the technology for development and regulatory review.
In a Phase II clinical trial published in the Annals of Surgical Oncology, the researchers tested the technology as part of cytoreductive surgery in patients with peritoneal metastases. However, a November 2023 UTSW press release noted that the technology is “tumor-agnostic and could potentially be used in other forms of cancer.” It is currently ready for Phase 3 trials, according to the OncoNano website.
More research and studies are needed to better understand this dynamic of cancer cells. Collectively, this research into cancer by different scientific teams is adding new insights into the way tumors originate and spread. At this time, these insights are not expected to lead to any new diagnostics tests that pathologists and clinical laboratories could use to detect cancer.
This new technology could replace needle biopsies and allow physicians to detect rejection of transplanted organs earlier, saving patients’ lives
Anatomic pathologists
may be reading fewer biopsy reports for patients with organ transplants in the
future. That’s thanks to a new technology that may be more sensitive to and
capable of detecting organ rejection earlier than traditional needle biopsies.
When clinicians can detect organ transplant rejection
earlier, patients survive longer. Unfortunately, extensive organ damage may
have already occurred by the time rejection is detected through a traditional
needle biopsy. This led a group of researchers at Emory University School of Medicine to
search for a better method for detecting organ rejection in patients with transplants.
The Emory researchers describe the method and technology
they devised in a paper published in Nature Biomedical
Engineering, titled, “Non-Invasive Early Detection of Acute Transplant
Rejection Via Nanosensors of Granzyme B Activity.” The new technology could
make it easier for clinicians to detect when a patient’s body is rejecting a
transplanted organ at an earlier time than traditional methods.
This technology also provides a running measure of processes,
so clinicians have more powerful tools for deciding on the most appropriate
dosage of immunosuppressant
drugs.
“Right now, most tests are aimed at organ dysfunction, and
sometimes they don’t signal there is a problem until organ function is below 50
percent,” Andrew
Adams, MD, PhD Co-Principal Investigator and an Associate Professor of Surgery
at Emory University School of Medicine, in a Georgia
Institute of Technology news release.
How the Technology Works
The method that Adams and his colleagues tested involves the
detection of granzyme B,
a serine protease
often found in the granules of natural killer cells
(NK cells) and cytotoxic
T cells. “Before any organ damage can happen, T cells have to produce granzyme
B, which is why this is an early detection method,” said Gabe Kwong, PhD, Assistant
Professor in the Wallace H. Coulter Department of Biomedical Engineering at
Georgia Tech and Emory University, in the news release.
The new technology is made up of sensor nanoparticles in the
shape of a ball with iron oxide in the middle. Amino acids stick out of the
ball like bristles. Each amino acid has a fluorescent molecule attached to the
tip.
The nanoparticles are injected into the patient. Their size
prevents them from gathering in the patient’s tissue or from being flushed out
through the kidneys. They are designed to accumulate in the tissue of the
transplanted organ.
If the T cells in the transplanted organ begin to produce
granzyme B, the amino acids break away from the nanoparticles, releasing the
fluorescent molecules attached to their tips. Those molecules are small enough
to be processed through the kidneys and can be detected in the patient’s urine.
Pathologists Play Crucial Role on Transplant Teams
Anatomical pathologists (histopathologists in the UK) are key
members of transplant teams for many reasons, including their ability to assess
biopsies. The current method for detecting organ transplant rejection involves
needle biopsies. It is considered the gold standard.
However, according to a paper published in the International
Journal of Organ Transplantation Medicine: “Although imaging studies
and laboratory findings are important and helpful in monitoring of the
transplanted liver, in many circumstances they are not sensitive enough. For
conditions such as rejection of the transplant, liver histology remains the
gold-standard test for the diagnosis of allograft dysfunction. Therefore,
histopathologic assessments of allograft liver
biopsies have an important role in managing patients who have undergone liver
transplantation.”
There are two main problems with needle biopsies. The first,
as mentioned above, is that they don’t always catch the rejection soon enough.
The second is that the needle may cause damage to the transplanted organ.
“The biggest risk of a biopsy is bleeding and injury to the transplanted organ,” noted Andrew Adams, MD, PhD (above), Co-Principal Investigator and an Associate Professor of Surgery at Emory University School of Medicine, in the Georgia Tech news release. “Then there’s the possibility of infection. You’re also just taking a tiny fraction of the transplanted organ to determine what’s going on with the whole organ, and you may miss rejection or misdiagnose it because the needle didn’t hit the right spot,” he added.
And, according to Kwong, even though biopsies are the gold
standard, the results represent one moment in time. “The biopsy is not
predictive. It’s a static snapshot. It’s like looking at a photo of people in
mid-jump. You don’t know if they’re on their way up or on their way down. With
a biopsy, you don’t know whether rejection is progressing or regressing.”
Future Directions of Emory’s Research
The research conducted by Adams and Kwong, et al, is in its
early stages, and the new technology they created won’t be ready to be used on patients
for some time. Nevertheless, there’s reason to be excited.
Nanoparticles are not nearly as invasive as a needle biopsy.
Thus, risk of infection or damaging the transplanted organ is much lower. And Emory’s
technology would allow for much earlier detection, as well as giving clinicians
a better way to adjust the dose of immunosuppressant drugs the patient takes.
“Adjusting the dose is very difficult but very important
because heavy immunosuppression increases occurrence of infections and patients
who receive it also get cancer more often,” said Kwong. The new technology
provides a method of measuring biological activity rates, which would give
clinicians a clearer picture of what’s happening.
The Emory team’s plan is to enhance the new sensors to
detect at least one other major cause of transplant rejection—antibodies. When
a patient’s body rejects a transplanted organ, it produces antibodies to
neutralize what it sees as a foreign entity.
“Antibodies kill their target cells through similar types of
enzymes. In the future, we envision a single sensor to detect both types of
rejection,” said Kwong.
Adams adds, “This method could be adapted to tease out
multiple problems like rejection, infection, or injury to the transplanted
organ. The treatments for all of those are different, so we could select the
proper treatment or combination of treatments and also use the test to measure
how effective treatment is.”
This line of research at Emory University demonstrates how
expanding knowledge in a variety of fields can be combined in new ways. As this
happens, medical laboratories not only get new biomarkers that can be
clinically useful without the need for invasive procedures like needle biopsies,
but these same biomarkers can guide the selection of more effective therapies.
Advances in artificial cell architecture and complex function may make it possible to develop a way for pathologists to deliver biomarkers into living cells to diagnosis diseases and monitor patient response to therapies
For the first time, researchers have used polymers to produce an artificial eukaryotic cell with working organelles. Like a living cell, it successfully performed multiple chemical reactions. The importance for pathologists and clinical laboratory professionals is that the same technology could allow scientists to develop different ways to deliver biomarkers into cells to reveal diagnostic information—and perhaps even track a patient’s progress in therapy.
Dutch Researchers Get Closer to Unlocking the Complexity of a Living Cell (more…)
