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Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.

ABSTRACT: 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 antigen-specific CTL immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs.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.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.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.

SUBMITTER: Wu CY

PROVIDER: S-EPMC3946442 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.

Wu Chao-Yi CY Yang Li-Hua LH Yang Huang-Yu HY Knoff Jayne J Peng Shiwen S Lin Yi-Hsin YH Wang Chenguang C Alvarez Ronald D RD Pai Sara I SI Roden Richard B S RB Hung Chien-Fu CF Wu T-C TC

Clinical cancer research : an official journal of the American Association for Cancer Research 20131203 3

<h4>Purpose</h4>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 antigen-specifi ...[more]

PMID: 24300786

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Project description:Simple Summary Gastrointestinal stromal tumors are considered to be insensitive to radiotherapy. However, with the development of radiation techniques and the accumulation of cases, some studies have indicated that radiotherapy could help achieve objective response in advanced or metastatic gastrointestinal stromal tumors. Therefore, it is necessary to conduct a systematic review to reassess the role of radiotherapy in gastrointestinal stromal tumors. The purpose of this study was to draw the attention of scholars and clinicians to radiotherapy and promote further research on radiotherapy in gastrointestinal stromal tumors. Abstract Gastrointestinal stromal tumors (GISTs) are considered insensitive to radiotherapy. However, a growing number of case reports and case series have shown that some lesions treated by radiotherapy achieved an objective response. The aim of the study was to perform a systematic review of all reported cases, case series, and clinical studies of GISTs treated with radiotherapy to reevaluate the role of radiotherapy in GISTs. A systematic search of the English-written literature was conducted using PubMed, Web of Science, and Embase databases. Overall, 41 articles describing 112 patients were retrieved. The included articles were of low to moderate quality. Bone was the most common site treated by radiotherapy, followed by the abdomen. In order to exclude the influence of effective tyrosine kinase inhibitors (TKIs), a subgroup analysis was conducted on whether and which TKIs were concurrently applied with radiotherapy. Results showed that radiotherapy alone or combined with resistant TKIs could help achieve objective response in selected patients with advanced or metastatic GISTs; however, survival benefits were not observed in the included studies. Pain was the most common symptom in symptomatic GISTs, followed by neurological dysfunction and bleeding. The symptom palliation rate was 78.6% after excluding the influence of effective TKIs. The adverse reactions were mainly graded 1–2. Radiotherapy was generally well-tolerated. Overall, radiotherapy may relieve symptoms for GIST patients with advanced or metastatic lesions and even help achieve objective response in selected patients without significantly reducing the quality of life. In addition to bone metastases, fixed abdominal lesions may be treated by radiotherapy. Publication bias and insufficient quality of included studies were the main limitations in this review. Further clinical studies are needed and justified.

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Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.

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Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.

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