Cancer Research and Treatment

Original Articles

IFITM1 Influences Natural Killer Cell–Mediated Cytotoxicity by Modulation of HLA Class I Expression in Triple-Negative Breast Cancer Cells: Heejin Lee, Chanyeon Park, Keunsoo Kang, Soon Auck Hong, Gyungmin Cho, Inyoung Cheon, Young-Ho Ahn, Jung-Sook Yoon, Yoon Ho Ko, Hye Sung Won; Received June 30, 2025 Accepted September 23, 2025 Published online September 25, 2025; DOI: https://doi.org/10.4143/crt.2025.444 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Interferon-induced transmembrane protein 1 (IFITM1) is associated with a poor prognosis in triple-negative breast cancer (TNBC); however, the mechanisms by which IFITM1 contributes to oncogenesis in TNBC are unclear.
Materials and Methods
We established two stable cell lines: IFITM1-overexpressing cell line (MB-231-IFITM1-OE) and IFITM1 knockdown cell line (BT-20-IFITM1-KD). The transcriptional activity of β-catenin and the cytotoxic activity of natural killer (NK) cells were evaluated using the luciferase assay and the lactate dehydrogenase cytotoxicity assay. The expression of IFITM1, β-catenin, and human leukocyte antigen (HLA) class I was assessed by immunohistochemistry in patients with TNBC.
Results
Knockdown of IFITM1 in BT-20 cells reduced cell proliferation and ectopically expressed IFITM1 in MB-231 cells increased cell proliferation. RNA sequencing analysis revealed that IFITM1 expression positively correlated with the Wnt/β-catenin signaling pathway and NK cell–mediated cytotoxicity. MB-231-IFITM1-OE cells showed increased β-catenin transcriptional activity and NK cell cytotoxic activity compared with controls, while transient knockdown of IFITM1 in MB-231-IFITM1-OE cells led to a decrease in β-catenin transcriptional activity and NK cell cytotoxic activity. MB-231-IFITM1-OE cells exhibited decreased HLA class I expression, which may have contributed to their increased susceptibility to NK cell–mediated lysis. β-catenin or JAK inhibitor reduced NK cell–mediated cytotoxicity via upregulation of HLA class I. Patients with IFITM1 overexpression showed a trend toward increased β-catenin positivity and HLA class I negativity.
Conclusion
IFITM1 overexpression was associated with Wnt/β-catenin signaling and NK cell–mediated cytotoxicity via downregulation of HLA class I in TNBC cells, suggesting that IFITM1 might have immunoregulatory effects on the tumor microenvironment.

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Expression of Immunoproteasome Subunit LMP7 in Breast Cancer and Its Association with Immune-Related Markers: Miseon Lee, In Hye Song, Sun-Hee Heo, Young-Ae Kim, In Ah Park, Won Seon Bang, Hye Seon Park, Gyungyub Gong, Hee Jin Lee; Cancer Res Treat. 2019;51(1):80-89. Published online February 26, 2018; DOI: https://doi.org/10.4143/crt.2017.500

Purpose
In the presence of interferon, proteasome subunits are replaced by their inducible counterparts to form an immunoproteasome (IP) plays a key role in generation of antigenic peptides presented by MHC class I molecules, leading to elicitation of a T cell‒mediated immune response. Although the roles of IP in other cancers, and inflammatory diseases have been extensively studied, its significance in breast cancer is unclear.
Materials and Methods
We investigated the expression of LMP7, an IP subunit, and its relationship with immune system components in two breast cancer cohorts.
Results
In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress-associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]). Patients with higher LMP7 expression had better disease-free survival outcomes than those with no or low expression in the positive lymph node metastasis group (p=0.041).
Conclusion
Close association between the TIL levels and LMP7 expression in breast cancer indicates that better antigen presentation through greater LMP7 expression might be associated with more TILs.

Citations

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