By looking at the immune system in whole blood at a single-cell level, Stanford researchers Martin Angst, Brice Gaudilliere and Nima Aghaeepour have been able to identify patient-specific immune signatures that predict the trajectory of their surgical recovery. The group uses high parameter mass cytometry technology developed at Stanford, combined with deep phenotyping and advanced bio-computational methods, to study how the human immune system responds and adapts to surgical trauma. By pinpointing specific immune phenotypes that are predictive of adverse postoperative outcomes, they hope to apply this knowledge to developing immune-modulating therapies that can be applied before surgery to improve recovery.
“We were interested in whether we could interrogate the patient’s immune system ahead of surgery and make predictions about their recovery,” said Martin Angst, MD, professor, anesthesiology, perioperative and pain. “Using high dimensional mass cytometry, we have recently shown that the signaling behavior of specific immune cells measured before surgery in patients’ blood predicted the speed at which they recovered form surgery.”
The team used a deep-phenotyping approach to measure various functional outcomes of patients undergoing major joint replacements and abdominal surgery. How quickly do they heal? How soon do they regain functionality?
“Everyone knows your immune system plays a role in how you recover from surgery,” said Gaudilliere, MD, PhD, assistant professor, anesthesiology, perioperative and pain. “But if you talk to a surgeon or anesthesiologist, and ask them if they take a patient’s immune system into consideration when they provide care, the answer is not at all.”
Instead, these physicians commonly look at a number of clinical and physiological parameters such as a patient’s age and pre-existing disease burden to predict perioperative outcomes. But all of these factors combined cannot accurately predict a patient’s functional recovery, said Angst. “Identified immune signatures did predict up to 50 percent of the variability in how patients recover, resolve pain and regain function.”
The team is able to define patient populations at risk based on their immune profile in peripheral blood. “We can precisely define these immunological states, looking at how every immune cell is behaving in response to surgery,” said Gaudilliere. “We should be able to use this information very practically in a clinical setting.”
Public health implications
“There are over 40 million surgeries a year in the US alone, and not everyone who has surgery recovers well,” said Angst. “Some may not go back to work, others might not be functional and others are fatigued for months. To us, that is a big public health issue.” That is what motivates their research.
About six years ago, this idea of harnessing immune information and bringing it into clinical care began germinating amongst Angst and Gaudilliere. Fueled by the support of their department chair Ron Pearl, MD, they partnered with computational scientist Nima Aghaeepour, PhD. The three began collaborating with Garry Nolan’s lab, which developed mass cytometry. This technology can measure 50 parameters per single cell, a vast improvement from standard flow cytometry assays, which could measure just six to 15 parameters per single cell.
“High dimensional cytometry allows you to look at the entire immune system, at how these immune cells are functioning with extreme resolution,” said Gaudilliere, “and then you can define these patient-specific immune states based on understanding how these immune cells behave. You’re not just looking at a marker that is going up or down,” he said. “You’re looking at how a certain biological process unfolds and you can therefore target it.”
The ability to assess the functionality of these immune cells cannot be over emphasized, said Aghaeepour. “These are cells that can be modified, that can be programmed to do something in your body, to change the biological processes that are happening.”
The long-term goal of their exploratory research is to create a reliable test physicians can use to predict patient recovery and make decisions about surgical timing and care. They also imagine a point where the information gleaned from patient-specific immune monitoring can be used to modulate a patient’s particular immune response before surgery to improve recovery.
“Immune cells tell us a lot about an individual’s biology and tell us about health risks in these patients such as slow functional recovery from surgery,” said Angst. “There is this conviction in our group now that we can measure this relevant biology and meaningfully link it to how an individual patient recovers from surgery.”