Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Sung Yong Lee, Jee Youn Oh, Tae Heung Kang, Hyun Seock Shin, Max A. Cheng, Emily Farmer, T. C. Wu, Chien Fu Hung

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number41
JournalJournal of Biomedical Science
Volume26
Issue number1
DOIs
Publication statusPublished - 2019 May 27

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Papillomavirus Vaccines
Endoplasmic Reticulum Stress
T-cells
Therapeutic Uses
Calreticulin
T-Lymphocytes
Antigens
Tumors
DNA Vaccines
Bearings (structural)
Neoplasms
Cytotoxicity
Therapeutics
Cells
Vaccine Potency
CD8 Antigens
Immune system
Combined Modality Therapy
Cell proliferation
Neoplasm Antigens

Keywords

  • 3-bromopyruvate
  • CD8 T cells
  • CHOP
  • Endoplasmic reticulum stress
  • GRP78
  • HPV
  • HPV16
  • pcDNA3-CRT/E7
  • Therapeutic HPV vaccine

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

Cite this

Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines. / Lee, Sung Yong; Oh, Jee Youn; Kang, Tae Heung; Shin, Hyun Seock; Cheng, Max A.; Farmer, Emily; Wu, T. C.; Hung, Chien Fu.

In: Journal of Biomedical Science, Vol. 26, No. 1, 41, 27.05.2019.

Research output: Contribution to journalArticle

Lee, Sung Yong ; Oh, Jee Youn ; Kang, Tae Heung ; Shin, Hyun Seock ; Cheng, Max A. ; Farmer, Emily ; Wu, T. C. ; Hung, Chien Fu. / Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines. In: Journal of Biomedical Science. 2019 ; Vol. 26, No. 1.
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AU - Cheng, Max A.

AU - Farmer, Emily

AU - Wu, T. C.

AU - Hung, Chien Fu

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