Interleukin-12 activated CD8+ T cells induces apoptosis in breast cancer cells and reduces tumor growth

• Published in: Biomedicine & pharmacotherapy 2016-12, Vol.84, p.1466-1471
• Main Authors: Yang, Shi-Xin, Wei, Wen-Song, Ouyan, Qian-Wen, Jiang, Qi-Hua, Zou, Yu-Feng, Qu, Wei, Tu, Jian-Hong, Zhou, Zhi-Bing, Ding, Hao-Long, Xie, Chun-Wei, Lei, Qiu-Mo, Zhong, Cheng-Ren
• Format: Article
• Language: English
• Subjects: 4T1 cells; Animals; Apoptosis - drug effects; Apoptosis - physiology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CD8+ cells; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Female; Interferon-γ; Interleukin-12; Interleukin-12 - pharmacology; Interleukin-12 - therapeutic use; Internal Medicine; Medical Education; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Nude; Tumor Burden - drug effects; Tumor Burden - physiology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2016.10.046

Abstract During the past two decades, cytokines have emerged as key molecules to modulate innate and adaptive immunity and mediate anti-tumor activity. Although multiple cytokine types are implicated for such anti-tumor activity in several cancer types, it remains largely unknown in breast cancer. In this study, cytokines that are prior known for antitumor activity in different cancer types were examined against breast cancer using a 4T1 cells based xenograft-model. Our results showed Interleukin-12 (IL-12) (500 ng/mouse) significantly suppressed the growth of tumors, while other cytokines showed minimal suppression. Subsequent molecular analysis by flow cytometry and immunohistochemistry confirmed the CD8+ cells infiltration and Interferon-γ (IFN-γ) production by them in tumor environment. In addition, we observed that IFN-γ production by activated CD8+ cells directly induced apoptosis in tumor cells, which together indicate that IL-12 causes CD8+ cells to infiltrate and secrete IFN-γ in tumor environment, which induce apoptosis in them and causes tumor growth suppression. Furthermore, we showed that lower dosage of IL-12 and chemotherapy drug tamoxifen combinations enhanced the tumor suppression as opposed to single treatments, and thereby propose an alternate option for high dosage associated effects for both drug and cytokine treatments.