Novel immunotherapy mechanism suppresses breast cancer development

BOSTON – Researchers have discovered the mechanism by which specific immune cells can block breast cancer development and even suppress a developed tumor. In mice studies, the team observed that CD4+ T helper (Th) 2 cells reverted high-grade breast tumors to making cells similar to a non-cancerous breast gland. The research is published in a paper in the Journal of Experimental Medicine.

“We showed that  CD4+ T helper 2 cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells,” says lead author Shawn Demehri, MD, PhD, principal investigator at the Center for Cancer Immunology and Cutaneous Biology Research Center of Massachusetts General Hospital. Demehri’s laboratory is focused on developing methods using the body’s immune system to prevent cancer development and cancer recurrence.

In this research, Demehri and colleagues discovered that the Th2 cells force the breast cancer cells to differentiate into tissue resembling fibrocystic breast lesions. “The Th2 cells force the cancer cells to go back to their original programming of making a breast gland that has no potential for growth or metastasis,” he says. Once the Th2 cells are stimulated to infiltrate breast cancer they release three cytokines, IL-3, IL-5, and GM-CSF, that directly reprogram the tumor cells into low-grade, fibrocystic-like structures. They are not normal breast gland cells, instead resembling fibrocystic tissues often seen on mammograms.

This work builds on Demehri’s 2016 discovery that a cytokine called thymic stromal lymphopoietin (TSLP) is essential for activating CD4+  positive T lymphocytes against breast cancer. This cytokine has been mostly investigated for its role in asthma and atopic dermatitis. The team discovered the mechanism by which TSLP-activated T cells block breast cancer development, leading to the idea that this novel mode of immunotherapy would be effective in breast cancer. Now that the team knows that CD4+ T helper 2 cells are directly transforming breast cancer cells in mice they plan to initiate a study among breast cancer patients.

“The future of this might be using mRNA technology,” explains Demehri, such as using TSLP cytokine mRNA to deliver the CD4+ Th2 cells to the breast cancer where it would be expressed locally in the breast tissue. “We would hope to see the same benefit we saw in mice in terms of driving the breast cancer cells back to a non-lethal tissue and perhaps prevent breast cancer recurrence.”

Funding was provided by grants from the Burroughs Wellcome Fund, American Cancer Society Institutional Research Grant, Breast Cancer Alliance, ESSCO MGH Breast Cancer Research Fund and NIH.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of “America’s Best Hospitals.” MGH is a founding member of the Mass General Brigham health care system.