Sylvester Cancer investigators identify potential new targets to overcome treatment resistance in aggressive breast cancer

MIAMI, FLORIDA (March 27, 2023) – Researchers with the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and collaborators have shown that immature Natural Killer (NK) cells are present in patients with triple-negative breast cancer (TNBC) and likely promote, instead of inhibit, disease progression in this cancer type.  

Their study, featured March 8 in Science Translational Medicine, could help clinicians combat treatment resistance in TNBC, one of the most aggressive breast tumors, by identifying certain NK cells as potential therapeutic targets.

NK cells are generally considered an effective contributor to anti-tumor immune responses. “However, not all NK cells are created equal,” said Rumela Chakrabarti, Ph.D., associate professor with Sylvester’s Tumor Biology Program and corresponding author of the study. “Immature NK cells were present in tissue samples from patients with triple-negative breast cancer and correlated with a worse prognosis for this patient subset.”

BACKGROUND

Breast cancer is the most frequently diagnosed cancer and remains the second-leading cause of cancer-related deaths among women in the U.S., with an estimated 275,000-plus new cases reported in 2020.

TNBC, which accounts for 10% to 15% of all breast cancers, is characterized by the lack of estrogen and progesterone receptors, as well as a protein called human epidermal growth factor (HER2). It has higher rates of recurrence and metastases than other breast cancers, and current treatments are often ineffective due to the absence of hormone receptors and HER2 proteins as therapeutic targets.

TNBC most commonly afflicts women under age 40, Black women and those with the BRCA1 gene mutation, according to the American Cancer Society.

METHODOLOGY

Chakrabarti and research colleagues were able to identify these rogue NK cells by using powerful RNA sequencing to distinguish cell variation at the single-cell level in patient tissue samples. Traditionally, researchers have used bulk RNA sequencing for this identification, but that method can miss finding these unique NK cells within the tumor microenvironment.

Using an innovative mouse model, the researchers also showed that NK cells promoted, rather than prevented, tumor progression in mice. By depleting these cells or inhibiting Wnt ligand secretion from NK cells to prevent faulty cell signaling that can cause gene disruption and cancer, researchers were able to block this effect in mice. “That suggests that immature NK cells represent a potential therapeutic target for women with TNBC,” Chakrabarti said.

MORE AUTHOR COMMENTS

Chakrabarti thinks this study could be a “game-changer” for TNBC patients. “Resistance to immunotherapy or chemotherapy poses a big problem for these patients, as few of them respond favorably to current treatments,” she explained. “Finding better drug targets is of paramount importance to improve survival rates.”

This study may pave the way to that goal. “Blocking immature NK cells sensitized tumors to chemotherapy in combination with immunotherapy in our mouse models,” Chakrabarti said, “opening new avenues for effective treatment.”

WHAT’S AHEAD

Chakrabarti and colleagues are focusing on how rogue NK cells are created within the tumor microenvironment of aggressive TNBC and their interaction with other immune cells. Their lab also is examining use of the FDA-approved drug LGK-974 to sensitize TNBC tumor cells to chemotherapy and immunotherapy, potentially leading to new and better therapies.  

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ADDITIONAL AUTHORS / INSTITUTIONS: The full list of authors and institutions participating in this research is published with the article.

FUNDING: This study was supported by grants from the American Cancer Society (RSGDDC-133604 to R.C.); the Emerson Collective Fund, University of Pennsylvania (20200315113131 to R.C.); the National     Cancer Institute (R01CA237243 to R.C.); and the Rita Allen Scholar Award, the Pershing Square Sohn Prize for Cancer Research, NIH/NCI grant R01CA248158-01 and NIH/NIA grant R01 AG069727-01 (all to C.O.D.S.).

COMPETING INTERESTS: The authors declare that they have no competing interests.

DOI: 10.1126/scitranslmed.abl4414

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