Above: Tumor cells (magenta) are shown surrounded by immune cells, including the macrophages (red) found to play an important role in fighting estrogen receptive-positive breast cancer.

Immune cells of various stripes have long been known to work together and even sub in for one another, in a pinch—pretty neighborly, you might say.

Recently, in a study of certain types of breast cancer, immune cells were spied not only acting neighborly, but putting down stakes together in cooperative little cancer-fighting “neighborhoods.” Cells called macrophages seemed to play an underappreciated role in many of these wee communities. That’s according to a Nature Cancer paper published in March by a team of investigators from the University of Pittsburgh and UPMC. If these insights bear out, they could point the way toward a new approach for drug development in certain tough-to-treat cancers.

It started about six years ago, when the paper’s first author, Sayali Onkar (PhD ’22), was embarking on a new research project, comentored by Pitt’s Steffi Oesterreich, a PhD and the Shear Family Foundation Professor in Breast Cancer Research, and Dario Vignali, a PhD, Distinguished Professor and chair of immunology. (Onkar graduated in December 2022 and is now a senior scientist at Mount Sinai Icahn School of Medicine.)

In some cancers, tumors respond well to immunotherapy, which leverages the body’s own immune response to thwart the disease. Unfortunately, Onkar explains, these drugs don’t work well for most breast cancers, especially those that are estrogen receptor–positive (ER+), meaning they need estrogen to grow. Most immunotherapy drugs work by boosting T cells, which ER+ breast cancers generally see much less action from, compared to other kinds of breast cancer.

Oesterreich, Onkar and Vignali decided to dig deeper into other groups’ recent findings about the role of macrophages in ER+ tumors.

First, Onkar collected samples from patients with two subtypes of ER+ tumors, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), with help from collaborators Priscilla McAuliffe, assistant professor of surgery, and Peter Lucas, professor and vice chair of pathology and professor of pediatrics.

Onkar then isolated, stained and analyzed the immune cells in each sample to come up with counts of a variety of immune cell types. She found that macrophages were, indeed, the clear frontrunners, especially in ILC.

Next, using expertise from the National Surgical Adjuvant Breast and Bowel Project, a clinical-trials cooperative, the team took a look at these tumor types in their environs—called the tumor microenvironment—with an eye on their immunological architecture.

“We realized the immune cells weren’t just scattered randomly,” says Onkar. “We started picking up certain patterns.” So they enlisted teams of biostatisticians and bioinformaticians led by Pitt’s Hatice Osmanbeyoglu and George Tseng, respectively. The researchers cataloged the neighborhoods into types, then compared those types to patients’ outcomes.

Some of these little locales, they found, seem to be better at tamping down tumors than others. That’s when the potential for a new, exciting avenue opened up.

Take, for example, a biological neighborhood associated with worse outcomes, says Oesterreich. “Maybe you can identify something they secrete, and block that, because that interaction inhibits killing of the tumor cells, right?”

In IDC, one kind of neighborhood was populated by macrophages that were cozying up to certain T cells (those famous cancer killers) and working in concert to result in better outcomes for patients. And in another kind of neighborhood, in ILC, macrophages were sending T cells packing. All told, the team identified seven distinct types of neighborhoods in IDC and ILC.

This study is just the latest among many from Oesterreich’s lab building the case that ER+ ILC and IDC, which are generally thrown into the same biomedical bucket, are actually very different. “By testing our hypothesis that IDC and ILC differ in their immune response, we can inform where we should focus attention for development of novel approaches,” Vignali says.

Next, the Pitt scientists aim to create animal models to study these neighborhoods in action. And at some point, Oesterreich says, they would love to explore another new realm: neighborhood maps meet the power of AI.

“Seeing if we can find patterns of how different tumor cells are spatially localized, and if that, potentially, is associated with unique responses to immune cells? I think that would be really, really cool to do.”

Read more from the Fall 2023 issue.