Cancer Res Treat.  2022 Oct;54(4):1111-1120. 10.4143/crt.2021.1017.

The Association of Estrogen Receptor Activity, Interferon Signaling, and MHC Class I Expression in Breast Cancer

• Song IH
• Kim YA
• Heo SH
• Bang WS
• Park HS
• Choi Yh
• Lee H
• Seo JH
• Cho Y
• Jung SW
• Kim HJ
• Ahn SH
• Lee HJ
• Gong G

• KMID: 2534190
• DOI: http://doi.org/10.4143/crt.2021.1017

Abstract

Purpose
The expression of major histocompatibility complex class I (MHC I) has previously been reported to be negatively associated with estrogen receptor (ER) expression. Furthermore, MHC I expression, level of tumor-infiltrating lymphocytes (TILs), and expression of interferon (IFN) mediator MxA are positively associated with one another in human breast cancers. This study aimed to investigate the mechanisms of association of MHC I with ER and IFN signaling.
Materials and Methods
The human leukocyte antigen (HLA)-ABC protein expression was analyzed in breast cancer cell lines. The expressions of HLA-A and MxA mRNAs were analyzed in MCF-7 cells in Gene Expression Omnibus (GEO) data. ER and HLA-ABC expressions, Ki-67 labeling index and TIL levels in tumor tissue were also analyzed in ER+/ human epidermal growth factor receptor 2 (HER2)- breast cancer patients who randomly received either neoadjuvant chemotherapy or estrogen modulator treatment followed by resection.
Results
HLA-ABC protein expression was decreased after β-estradiol treatment or hESR-GFP transfection and increased after fulvestrant or IFN-γ treatment in cell lines. In GEO data, HLA-A and MxA expression was increased after ESR1 shRNA transfection. In patients, ER Allred score was significantly lower and the HLA-ABC expression, TIL levels, and Ki-67 were significantly higher in the estrogen modulator treated group than the chemotherapy treated group.
Conclusion
MHC I expression and TIL levels might be affected by ER pathway modulation and IFN treatment. Further studies elucidating the mechanism of MHC I regulation could suggest a way to boost TIL influx in cancer in a clinical setting.

Keyword

Breast neoplasms; Estrogens; Receptors; Interferons; Major histocompatibility complex; Tumor-infiltrating lymphocytes

Figure

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  Fig. 1 The effect of estrogen signaling and interferon signaling on HLA-ABC expression. (A) The baseline HLA-ABC protein expression is higher in ER-negative MDA-MB-231 cell lines than in ER-positive MCF-7 and T47D cell lines. (B) After 24 or 48 hours of ICI treatment (1 to 10 μM), the ER protein expression decreased, and HLA-ABC protein increased in MCF-7 cells. (C) The HLA-ABC protein expression increased in MCF-7 cells 48 hours after 100 units/mL of IFN-γ treatment. ER, estrogen receptor; HLA, human leukocyte antigen; IFN, interferon; MHC I, major histocompatibility complex class I.

• 

  Fig. 2 HLA-ABC protein expression in the MDA-MB-231 cells. (A) Twenty-four or 48 hours after transfection with the hESR-GFP plasmid, MDA-MB-231 cells show ER expression and decreased HLA-ABC protein levels. (B) The HLA-ABC protein expression was markedly increased 48 hours after 100 units/mL of IFN-γ treatment in MDA-MB-231 cells. ER, estrogen receptor; HLA, human leukocyte antigen; IFN, interferon; MHC I, major histocompatibility complex class I.

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  Fig. 3 The changes of mRNA expression in MCF-7 breast cancer cells after ESR1 shRNA transfection. ESR1 expression decreased after transfection (A), and HLA-A and MxA expressions increased after transfection (B, C). HLA, human leukocyte antigen.

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  Fig. 4 The microscopic images of breast tissue before and after chemotherapy or estrogen modulator treatment. In the patient who received neoadjuvant chemotherapy (A), the quantity of TILs decreased and HLA-ABC expression was similar in the resection specimen compared with the pre-neoadjuvant biopsy specimens. By contrast, the TIL levels and HLA-ABC expression increased after estrogen modulator treatment in the patient who received estrogen modulator treatment (Nolvadex and Zoladex) (B) (A and B, ×400). HLA, human leukocyte antigen; TIL, tumor-infiltrating lymphocyte.

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  Fig. 5 The changes of ER and HLA-ABC expression and TIL levels. The TIL levels significantly decreased after chemotherapy, while the expression of ER decreased after estrogen modulator treatment. Compared with the chemotherapy group, HLA-ABC expression increased significantly after estrogen modulator treatment (Op). ER, estrogen receptor; HLA, human leukocyte antigen; Op, operation; TIL, tumor-infiltrating lymphocyte.

Reference

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