Immune response in colorectal cancer: What helps, what hurts?

One of the grant’s three principal investigators, Phipps will co-lead the project with Hutch molecular and genetic epidemiologist Dr. Ulrike “Riki” Peters, who launched GECCO in 2007, and Dr. Shuji Ogino, a pathologist/epidemiologist with Harvard Medical School and Brigham and Women’s Hospital. 

Together, the research team will drill down into T-cell response in colorectal cancer tumors.

“We’re looking at how that response differs according to a person’s lifestyle, according to their genetics and according to the biology of their tumor,” Phipps said. “How does your personal profile and the different aspects of your tumor biology relate to your T-cells’ response and, in turn, how does that T-cell response relate to your survival?”

The paths to cancer and precision medicine

The GECCO consortium investigates the various paths to colorectal cancer by following the genetic and biological breadcrumbs that lead to its development.

GECCO’s data coordinating center, housed at the Hutch, manages the individual-level genetic and epidemiological data of over 130,000 participants from 70 studies across North America, Australia, Asia and Europe. To date, the researchers have harmonized over 100 lifestyle, environmental, and clinical variables across these studies. They’ve also generated and harmonized over 40 million genetic variants across the genome for each of the 130,000 participants and are currently sequencing the tumor genome for a subset of 7,000 colorectal cancer cases.

“Together with our very committed collaborators, this international consortium has been able to develop a unique resource that does not exist anywhere else in the world,” says Tabitha Harrison, a Hutch genetic epidemiologist and GECCO’s coordinating center manager.  “This provides a powerful resource for addressing important research questions that no single study would be able to undertake alone.”

Among other things, the consortium’s work has led to the development of a risk prediction model to better pinpoint who needs early screening and who doesn’t. They’ve deciphered who might benefit from aspirin, or non-steroidal anti-inflammatory drugs, and who might not. In 2018, GECCO researchers identified 40 new colorectal cancer genetic risk variants, some of which are protective.

“All of this new information helps to inform decisions about interventions, such as screening or chemoprevention, to prevent cancer in healthy people,” said Peters. “This is the path to personalized medicine.”

GECCO investigates genetic variants as well as interactions between genes and lifestyle risk factors that can help promote or prevent colorectal cancer. These include good and bad gene-dietary interactions (i.e., what can happen when you eat vegetables versus red and processed meat) and good and bad gene-environmental interactions that occur as a result of smoking, alcohol use, exercise (or lack thereof), high or low body-mass index and other factors.

These interactions, both helpful and harmful, along with a person’s individual DNA — the bits you’ve inherited from your parents — all have an impact on your risk for developing cancer (which is how their risk-prediction model works).

These interactions also all have an impact on your body’s immune response to cancer.

Data that keeps on giving

For this study, GECCO researchers will analyze data from 2,500 colorectal cancer patients drawn from one of five large study cohorts: the Women’s Health Initiative, which also houses its data coordinating center at the Hutch; the Health Professionals Follow-up Study and Nurses’ Health Study, both based at Harvard; the Ontario Familial Colorectal Cancer Registry (part of the Colon Cancer Family Registry) and the Melbourne Collaborative Cohort Study.

The consortium has already done the germline genotyping and harmonized epidemiologic data for a variety of lifestyle factors and personal characteristics for all of the participating studies.

“So much of the foundation for this study has already been laid by GECCO and the existing studies,” Phipps said. “A lot of the data we’re using has already been collected.”

Case in the point, the Women’s Health Initiative’s LILAC study, short for “Life and Longevity After Cancer,” collected blood and tumor specimens from a segment of original WHI participants who went on to develop cancer.

The GECCO team will use data from this ancillary study — and others like it — along with all the other data they’ve amassed over the years.

“GECCO investigators have spent years gathering genetic and lifestyle data and sequencing it and looking at the microenvironment of the tumor,” Phipps said. “We have a great head start because of that.”

What they don’t have, though, is the T-cell data.

“That’s the data we need to answer our research question,” Phipps said. “What we’ll be doing now for all the studies is taking the tumor specimens and looking at the T-cell response.”

What helps and what hurts immune response?

“We know there are different aspects of lifestyle that can impact immune response overall, like physical activity or smoking,” Phipps said. “They can impact your ability to mount an immune response. We’re looking at how these types of behaviors impact the makeup of a T-cell response in a person’s colorectal cancer.”

The researchers will examine lifestyle factors from the five larger cohorts that can influence cancer risk and the body’s immune response: physical activity, smoking, alcohol use, body-mass index and aspirin use.

The GECCO team will also measure the density of certain types of gut bacteria, such as fusobacterium nucleatum (which we all have, but is more abundant in people with colorectal cancer) to analyze its effect.

“We think the density of those bacteria could down-regulate the anti-tumor T-cell response,” Phipps said. “The bacteria might suppress your T-cell response.”

Fred Hutch’s Tabitha Harrison, GECCO’s coordinating center manager and a member of the research team, called this study of the immune response “critical.”

“What we’re learning about inflammation, modulation and evasion of immune response in colorectal cancer makes it critical that we accurately measure the presence, density and the spatial architecture of immune cells in the tumor and the areas around the tumor — the tumor microenvironment,” she said.

Predicting and preventing cancers

By drilling down into the different types of T-cell subsets within each participants’ tumor — along with their various markers, which help to differentiate one from another — the researchers hope to learn if some T cells are better at beating back cancer than others.

“Is it the memory cytotoxic T cell? The regulatory T cell? Which are most important for survival? That’s what we’re trying to answer,” Phipps said. “We’ll use multiplex assays to collect the T-cell response. Ultimately, we hope to better understand where T-cell response comes from and how we can predict it.”

From a prevention standpoint, she said, public health researchers could then provide much more precise guidance to the public.

“Not all cancers can necessarily be prevented,” she said. “But if people do get a cancer, you might be able to tell them ‘Try X, Y and Z because your prognosis may be better, your body may be able to better mount the right kind of T-cell response.’”

The study, which Phipps said is taking the research in an “exciting new direction,” might also help people better understand just how complicated cancer is — and why scientists make the health recommendations they do.

“There’s never a single solitary culprit; it’s a combination of factors layered on top of one another,” she said. “Our goal is to pull back some of those layers and unravel the mechanisms. Why would cigarette smoking be associated with poorer colorectal cancer survival? Part of it may be that cigarette smoking has an impact on your T-cell response. And that has an impact on your survival.”