- 作者: Sung Yong Lee, Jee Youn Oh, Tae Heung Kang, Hyun Seock Shin, Max A. Cheng, Emily Farmer, T.-C. Wu and Chien-Fu Hung
- 作者服務機構: 1. Department of Respiratory & Critical Care Medicine, Korea University Medical Center, 73 Inchon-ro, Seongbuk-gu, Seoul, 02841, South Korea 2. Department of Immunology, Konkuk University Medical Center, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea 3. Department of Pathology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul, 02841, South Korea 4. Department of Pathology, Johns Hopkins Medical Institutes, 1550 Orleans Street, Cancer Research Building II, Baltimore, MD 21287, USA 5. Department of Obstetrics & Gynecology, Johns Hopkins Medical Institutes, 1550 Orleans Street, Cancer Research Building II, Baltimore, MD 21287, USA 6. Department of Molecular Microbiology & Immunology, Johns Hopkins Medical Institutes, 1550 Orleans Street, Cancer Research Building II, Baltimore, MD 21287, USA 7. Department of Oncology, Johns Hopkins University School of Medicine, CRB II Room 307, 1550 Orleans Street, Baltimore, MD 21287, USA
- 中文摘要:
- 英文摘要:
Background
Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and also has the capacity to activate cells of the adaptive immune system. Multimodal treatment methods that utilize and combine conventional cancer therapies with antigen-specific immunotherapies have emerged as promising approaches for the treatment and control of cancer. However, it is not well known whether endoplasmic reticulum stress-inducing agents can influence the efficacy of tumor antigen-targeting vaccines.
Methods
In the past, we developed a therapeutic human papillomavirus (HPV) DNA vaccine that encodes for calreticulin (CRT) linked to the HPV16 E7 antigen (CRT/E7). In this study, we utilize the CRT/E7 and further encode for an endoplasmic reticulum (ER) stress-inducing agent, 3-bromopyruvate (3-BrPA), in a preclinical model, by harnessing its potential to enhance HPV16 E7-specific CD8+ T cell immune responses as well as antitumor effects against E7-expressing tumors (TC-1 cells). E7-specific CD8+ T cells were added to evaluate the cytotoxicity of luciferase-expressing TC-1 tumor cells treated with 3-BrPA in vitro, as measured with an IVIS Luminescence Imaging System. We also determined the levels of ER stress markers in 3-BrPA-treated TC-1 cells. TC-1 tumor-bearing mice were treated with either 3-BrPA (10 mg/kg, intraperitoneal injection) and/or CRT/E7 DNA vaccine (30 μg/mouse).
Results
Treatment of E7-expressing TC-1 tumor cells with 3-BrPA induced significantly higher in vitro cytotoxicity and resulted in upregulation of endoplasmic reticulum stress markers (CHOP and GRP78). More importantly, combination treatment of 3-BrPA and the CRT/E7 DNA vaccine led to improved antigen-specific CD8+ T cell immune responses as well as therapeutic antitumor effects in TC-1 tumor-bearing mice.
Conclusions
Our data indicate that 3-BrPA can enhance therapeutic HPV vaccine potency in generating improved antigen-specific immune responses and antitumor effects. These findings have important implications for future clinical translation and provide novel strategies for the treatment of HPV-associated diseases. - 中文關鍵字:
- 英文關鍵字: HPV, HPV16, Therapeutic HPV vaccine, pcDNA3-CRT/E7, 3-bromopyruvate, Endoplasmic reticulum stress, CHOP, GRP78, CD8 T cells