A burgeoning type of “omics” called immunopeptidomics is providing researchers with a powerful approach to discovering new ways to train a person’s immune system to fight cancer.
In cancer research, the approach is being used to take an inventory of every flag on the surface of a cancer cell and determine what it is, if it is specific to the cancer, and if it can stimulate an immune response.
Dana-Farber researcher William Freed-Pastor, MD, PhD, a physician-scientist in the Dana-Farber Center for Gastrointestinal Oncology and Hale Family Center for Pancreatic Cancer Research at Dana-Farber, is using immunopeptidomics in collaboration with investigators at the Broad Institute and Koch Institute to find possible new ways to treat pancreatic cancer with immunotherapy. The method has helped them build a short-list of pancreatic-cancer-specific immune targets that could become the targets for new cancer therapies.
What does the word immunopeptidomics mean?
The term combines three ideas:
- Immunity: Immunity occurs when the immune system recognizes antigens that are foreign or unexpected, such as antigens that indicate an infection or cancer, and attacks them.
- Peptides: Antigens are peptides, which are protein fragments that come from the source of the infection or from the molecular machinery inside of a cancer cell, and can help the immune system identify the cell as diseased.
- Omics: Omics is an approach to science that involves taking an unbiased inventory of specific aspects of a cell to understand its inner workings more completely. For instance, proteomics inventories the proteins in a cell while immunopeptidomics inventories the antigens.
Why is immunopeptidomics important?
In cancer research, immunopeptidomics is an unbiased way to take an inventory of the antigens the immune system could use to identify and kill cancer cells. The inventory is unbiased because it doesn’t start with a short list of known targets that are suspect. Rather, the approach creates a list of all the targets that are present in a disease and enables an investigator to systematically home in on the ones that might be of interest.
By creating a full inventory of possible targets, immunopeptidomics can help researchers discover targets they did not know existed. These discoveries can lead to the development of completely new ideas for therapeutics.
“This is a way of taking a step back and asking, what are the targets that are actually there in human disease and then acting on what we find,” says Freed-Pastor.
How does this method work?
There are three main steps to immunopeptidomics:
- Start with many cells of interest, such as cancer cells, and extract all the antigens. Antigens are peptides, which are protein fragments that are presented on the outside of cells as flags that have the potential to alert the immune system. This process involves:
- Lysing the cells so that the molecules that present antigens on the surface, called human leukocyte antigen (HLA) molecules, float free.
- Isolating the HLA molecules bound to peptides.
- Separating the peptides from the HLA molecules.
- Next, use mass spectrometry to identify the antigens. Mass spectrometry creates a unique molecular signature for each antigen and can provide a sense of which antigens are present in abundance and which are scant. Some antigens may not be detected if they are too scant.
- Once the antigens are identified, determine which ones are immunogenic, meaning they can stimulate the immune system. Some antigens do not alert the immune system because they are seen as “self.” But antigens that are unfamiliar can grab the immune system’s attention and stimulate a response, which might be to kill the cell.
Investigators also might want to know where in the genome the antigens came from. For instance, an antigen might be a fragment of a mutant protein produced by a mutated gene. Or, as discovered by Dana-Farber’s Catherine Wu, MD, chief of the Division of Stem Cell Transplant and Cellular Therapies, it might come from an unexpected part of the genome, such as the non-protein-coding regions.
Together, this information can reveal how the antigens are related to cancer and help investigators home in on antigens that might make good immunotherapy targets.
What can investigators do with the results?
Knowing which antigens are common or possible on a specific type of cancer cell gives researchers a list of possible targets for treatment. More research is needed to determine if any given antigen is a good target, however.
A good target is one that is unique to the cancer and not seen on healthy cells. It also must be able to stimulate an immune response. Not all antigens do. Once a good target is found, work can begin to determine if it is possible to generate a therapeutic that targets it, such as a T-cell therapy specific to that antigen.
About the Medical Reviewer
Dr. Freed-Pastor is a medical oncologist and physician-scientist at Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT. He received his MD and PhD from Columbia University College of Physicians and Surgeons and subsequently completed residency in Internal Medicine at Massachusetts General Hospital and a fellowship in Medical Oncology at Dana-Farber Cancer Institute. Following a postdoctoral research fellowship in the laboratory of Dr. Tyler Jacks at MIT, Dr. Freed-Pastor joined the staff of Dana-Farber Cancer Institute and Brigham and Women's Hospital. He specializes in the treatment of patients with gastrointestinal cancers, with a particular focus on pancreatic cancer. He also directs a research laboratory that studies the role of the immune system during pancreatic tumor development and applies these insights to develop novel therapeutic approaches that leverage the immune system for the treatment of pancreatic cancer.