Researchers Identify Potential Targets to Overcome Treatment Resistance in Aggressive Breast Cancer

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 type of cancer.

This is a conclusion of a study by researchers from the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and their collaborators. The study-results were featured in the March 8, 2023 edition of Science Translational Medicine and could help clinicians combat treatment resistance in TNBC, one of the most aggressive breast tumors, by identifying certain NK cells as potential therapeutic targets. [1].

The study was supported by grants from the American Cancer Society, the Emerson Collective Fund, the University of Pennsylvania, the National Cancer Institute and the Rita Allen Scholar Award, the Pershing Square Sohn Prize for Cancer Research.

Natural Killer or NK cells are generally considered an effective contributor to anti-tumor immune responses. “However, not all NK cells are created equal,” note 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,” Chakrabarti added.

Second leading cancer
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.

Triple-negative breast cancer, 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 2 (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.

Triple-negative breast cancer most commonly afflicts women under age 40, Black women and those with the BRCA1 gene mutation. [2]

Study design
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 single-cell RNA sequencing and functional analysis of multiple TNBC and basal tumor samples, the researchers observed a unique sub-cluster of Socs3^highCD11b⁻CD27⁻ immature NK cells that were present only in TNBC samples. The researchers noted that rather than preventing, these tumor-infiltrating NK cells promoted 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,” noted Chakrabarti.

“Game-changer” for the treatment of TNBC
Chakrabarti believes that based on the outcome of 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,” Chakrabarti explained. “Finding better drug targets is of paramount importance to improve survival rates,” she added.

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,” Chakrabarti concluded

What’s Next
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 LGK-974, a potent and specific small-molecule Porcupine (PORCN) inhibitor in clinical development by Novartis, to sensitize TNBC tumor cells to chemotherapy and immunotherapy, potentially leading to new and better therapies. LGK‑974, inhibits Wnt secretion, blocks Wnt/β‑catenin signaling and exert anti‑inflammatory effects by suppressing pro‑inflammatory gene expression in cancer cells. [3]

Clinical trials
A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands – NCT01351103

Reference
[1] Thacker G, Henry S, Nandi A, Debnath R, Singh S, Nayak A, Susnik B, Boone MM, Zhang Q, Kesmodel SB, Gumber S, Das GM, Kambayashi T, Dos Santos CO, Chakrabarti R. Immature natural killer cells promote progression of triple-negative breast cancer. Sci Transl Med. 2023 Mar 8;15(686):eabl4414. doi: 10.1126/scitranslmed.abl4414. Epub 2023 Mar 8. PMID: 36888695.
[2] Triple-negative Breast Cancer, Types of Breast Cancer. American Cancer Society (ACS). Online. Last accesses on Tuesday, March 29, 2023
[3] Tang Y, Jiang M, Chen A, Qu W, Han X, Zuo J, Xu G, Song Y, Chen C, Ke X. Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells. Mol Med Rep. 2021 Aug;24(2):550. doi: 10.3892/mmr.2021.12189. Epub 2021 Jun 3. PMID: 34080032; PMCID: PMC8185506.

Featured image: Breast cancer screening. Photo courtesy: © 2016 – 2023 Fotolia/Adobe. Used with permission.