Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors

Chao Yi Wu, Li Hua Yang, Huang Yu Yang, Jayne Knoff, Shiwen Peng, Yi Hsin Lin, Chenguang Wang, Ronald D. Alvarez, Sara I. Pai, Richard B.S. Roden, Chien Fu Hung, T. C. Wu

Research output: Contribution to journalArticle

Abstract

Purpose: Radiotherapy kills cancer cells by causing DNA damage, and stimulates a systemic antitumor immune response by releasing tumor antigen and endogenous adjuvant within the tumor microenvironment. However, radiotherapy also induces the recruitment of immunosuppressive myeloid cells, which can interfere with the antitumor immune responses elicited by apoptotic tumor cells. We hypothesized that local delivery of vaccine following radiotherapy will lead to the priming of antigenspecific CTL immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs. Experimental Design: Using several antigenic systems, we tested whether intratumoral injection of antigenic peptide/protein in irradiated tumors would be able to prime CTLs as well as load myeloid cells with antigen, rendering them susceptible to antigen-specific CTL killing. Results: We show that by combining radiotherapy and targeted antigenic peptide delivery to the tumor, the adjuvant effect generated by radiotherapy itself was sufficient to elicit the priming and expansion of antigen-specific CTLs, through the type I IFN-dependent pathway, leading to synergistic therapeutic antitumor effects compared with either treatment alone. In addition, using two different types of transgenic mice, we demonstrated that CTL-mediated killing of stromal cells in tumors by our approach is important for tumor control. Finally, we confirmed the efficacy of this approach in our preclinical model using two clinically tested therapeutic human papilloma virus (HPV) vaccines. Conclusions: These data serve as an important foundation for the future clinical translation of radiotherapy combined with a clinically tested therapeutic HPV vaccine for the control of HPV-associated cancers.

Original languageEnglish (US)
Pages (from-to)644-657
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number3
DOIs
StatePublished - Feb 11 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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