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. 2023 Sep;98(3):e13300.
doi: 10.1111/sji.13300. Epub 2023 May 24.

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti-breast cancer immunity: An in vitro study

Amirhossein Jahangiri  1 , Rana Ezzeddini  2 , Nazanin Zounemat Kermani  3 , Fariborz Bahrami  4 , Amir Salek Farrokhi  4
Affiliations
Free article

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti-breast cancer immunity: An in vitro study

Amirhossein Jahangiri et al. Scand J Immunol. 2023 Sep.
Free article

Abstract

Breast cancer (BC) is the most prevalent diagnosed cancer among women. Herceptin blocks the effects of Her-2 and tumour cell growth. Despite many achievements using Herceptin in Her-2+ invasive BC treatment, there are treatment failures and resistances. The signal transducer and activator of transcription 3 (STAT3) is persistently activated in BC and is associated with immune suppression and tumour cell proliferation. We evaluated whether STAT3 inhibition could increase Herceptin impact on in vitro reduction of immune checkpoint inhibitors and polarize T cells to a protective immune response. We treated SK-BR-3 cells with Herceptin and the STAT3-inhibitor (FLLL32) and assessed the apoptosis and expression of apoptosis-related proteins, VEGF, Her-2 and apoptosis targets of STAT3. PBMCs were isolated from healthy donors and co-cultured with SK-BR-3 cells in the presence or absence of Herceptin and FLLL32. PD-L1, CTLA-4, TIM-3 and T-cell intracellular cytokines were then evaluated. Our results demonstrated that STAT3 inhibition and Herceptin increased SK-BR-3 cell apoptosis, significantly. STAT3 inhibition through combination treatment had a more significant effect on regulating PD-1, TIM-3 and CTLA-4 expression on PBMCs. Alternatively, the combination of FLLL32 and Herceptin promoted T helper-1 protective immune response. The combination of FLLL32 and Herceptin suppress the expression of immune checkpoints and provoke the T-helper1 immune response in lymphocytes. Our analysis indicates STAT3 as a promising target that improves Herceptin's role in breast cancer cell apoptosis.

Keywords: CTLA‐4; Herceptin; PD‐1; STAT3; TIM‐3; breast cancer; immune response.

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