Taming “Gemini” Immune Cells—Tumor-Infiltrating Neutrophils

Researcher’s discovery of how tumor-infiltrating neutrophils may abet or kill colorectal cancers based on tumor grade uncovers 2 promising treatments.

Grantee: Ronen Sumagin, PhD
Institution: Northwestern University Feinberg School of Medicine in Chicago
Area of Focus: Metastasis and Microenvironment
Grant Term: 1/1/18 to 12/31/22

“Neutrophils are well known for their role in defending the body against invading pathogens. In my lab, we found that neutrophils play important roles in the transformation of healthy cells to cancer cells. When there is inflammation, neutrophils migrate into inflamed tissues, where they increase the occurrence of DNA mutations. They also slow the cell’s ability to repair itself, which ultimately increases the chance of developing cancer. Colorectal cancer is just one type of cancer associated with a high number of neutrophils within and around tumors.
As we continued to study the function of neutrophils in cancer, we learned that neutrophils can function as a double-edge sword. That is, they kill cancer cells under some circumstances, while under other circumstances, they help cancer evolve and grow. Thus, neutrophils are very attractive new targets for new or improved therapeutic approaches to battle cancer.
“In this study, we demonstrate that neutrophils migrating into developing colon tumors can shape the way cancer cells repair broken DNA. By doing so, neutrophils affect progression of colorectal cancer and its response to commonly used treatments known as DNA-repair targeted therapy.”—Ronen Sumagin, PhD

The Challenge: Neutrophils are a type of white blood cell that are among the first immune cells to defend the body against infection. They “rush” to kill harmful bacteria in the body and to areas that are inflamed, including inflammation caused from developing colorectal cancers.

Neutrophils already have a diagnostic role. Doctors may use the number of neutrophils in the bloodstream or in tumors to predict the severity of certain types of tumors and how they may response to chemotherapy.

But neutrophils have a dual nature. When they surround and enter, or infiltrate, tumors, they’re called tumor-infiltrating neutrophils. Colorectal cancers with these neutrophils are more aggressive, and patients with these cancers have worse clinical outcomes. No one understands why.

If researchers could learn more about how neutrophils affect colorectal cancers, their knowledge could help lead to the development of new cancer treatment and preventive strategies.

The Research: The lab of Ronen Sumagin, PhD, studies how neutrophils and other immune cells contribute to the development and progression of colorectal cancers. In a 2021 publication in Gastroenterology, he and his research team describe how they analyzed the effect of tumor-infiltrating neutrophils on cancer progression. They studied mouse models as well as human colorectal cancer tissues from biopsies from people with colorectal cancer who didn’t have a strong family history.

They identified a dual function of tumor-infiltrating neutrophils in colon cancer and demonstrated that neutrophils can be both anti-cancer and pro-cancer depending on colorectal tumor grade. Tumor grade describes how different cancer cells look and are arranged compared to healthy (typical) cells. The more abnormal and disorganized (atypical) they look, the higher the grade, and the more likely they are to grow quickly and spread.

Sumagin’s lab team found that in low-grade tumors, neutrophils slow overall tumor growth by shutting down a specific type of DNA repair in cancer cells.

Whereas, in high-grade tumors, they found neutrophils help the cancer cells survive and grow by promoting the activation of a certain type of DNA repair.

Why Does it Matter? These findings open the door to two possible new treatments for colorectal cancer.

One is to treat low-grade colorectal cancers with an existing FDA-approved drug to treat certain breast and ovarian cancers, olaparib (Lynparza).  

To treat high-grade colorectal cancers, Sumagin’s lab team recommends targeting a well-known DNA repair pathway that is “turned on” in cancer, but which is not currently used for therapeutic purposes.

These promising pre-clinical discoveries await additional research, including testing in humans.