Research Article Anti-HER2/Neu Antibody Therapy Inhibits HER2+ Breast Cancer by Blocking Myeloid-Derived Suppressor Cells Activity
by Jae-Hyeog Choi1*, SaeGwang Park2*, Xingguo Quan2*, Jin-Hee Park2, Myoung Joo Kang3, Yong June Lee3, Sung Sook Lee3, Sung-Nam Lim3, Jin Lee4, Tae-Hoon No4, So Young Jung5, Ki Hyang Kim6, Ji Young Lee6, Won Sik Lee6, Byeonghwa Bak (same as Byunghwa Park)7, JeongChul Hoi8, Il Hwan Kim3
1New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea.
2Department of Microbiology and Immunology, Inje University College of Medicine, Busan 47392, Republic of Korea.
3Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
4Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
5Department of Dermatology, Haeundae Paik Hospital, Inje University, Busan, Korea.
6Division of Oncology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan 47392, Republic of Korea.
7Division of Nephrology, Department of Internal Medicine, Hanbithospital, Busan, Republic of Korea.
8Department of Obstetrics and Gynecology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
*These authors contributed equally to the work.
*Corresponding author: IlHwan Kim, Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Jae-Hyeog Choi, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea.
Received Date: 15 May 2025
Accepted Date: 26 May 2025
Published Date: 28 May 2025.
Citation: Choi JH, Park S, Quan X, Park JH, Kang MJ, et al. (2025) Anti-HER2/Neu Antibody Therapy Inhibits HER2+ Breast cancer by blocking Myeloid-derived Suppressor Cells Activity. J Oncol Res Ther 10: 10285. https://doi.org/10.29011/2574-710X.10285.
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population playing a key role in tumor-related immune suppression. MDSCs are immature cells with myeloid markers CD11b and Gr1 in mice and accumulate in tumor-bearing mice, including HER2/neu+ breast cancers. We previously reported that tumor regression by anti-neu antibody requires both innate and adaptive immunity. MDSCs inhibit both immunity types and are immunosuppressive, particularly for T cells. However, the effect of anti-neu antibody on MDSCs remains unclear.
Methods: HER2+ TUBO tumor-bearing mice were treated with anti-neu antibody or control. MDSC populations were analyzed via flow cytometry, and immunosuppressive function by suppression assay. Tumors were analyzed using RT2-PCR array and RTPCR for gene expression related to MDSC activation, migration, and function. Additional mice received combination therapy with 5-FU or Zoledronic acid to assess enhanced MDSC inhibition and changes in MDSC and TAM (tumor-associated macrophage) populations.
Results: MDSCs decreased within 3 days after anti-neu antibody treatment in tumor and spleen, with tumor MDSCs declining one day earlier. Monocytic MDSCs were significantly reduced in both tissues (p>0.05). Anti-neu antibody also reduced MDSC immunosuppressive activity. Gene expression analysis showed decreased IL-1ß, VEGF, and CX3CL1, linked to MDSC activation and migration. The immunosuppressive factor IDO (Indoleamine 2,3-dioxygenase) was also reduced. Combination therapy with 5-FU further suppressed MDSCs and TAMs, resulting in better tumor suppression than antibody alone.
Conclusions: Tumor suppression by anti-neu antibody is associated with MDSC reduction via inhibition of key MDSC-related factors. MDSCs may be a therapeutic target to enhance Herceptin efficacy in breast cancer.
Keywords: Breast cancer, anti-HER2/neu antibody, Tumor microenvironment, Myeloid-derived suppressor cells, Combination therapy
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