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      Biological effects of radiation on cancer cells

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          Abstract

          With the development of radiotherapeutic oncology, computer technology and medical imaging technology, radiation therapy has made great progress. Research on the impact and the specific mechanism of radiation on tumors has become a central topic in cancer therapy. According to the traditional view, radiation can directly affect the structure of the DNA double helix, which in turn activates DNA damage sensors to induce apoptosis, necrosis, and aging or affects normal mitosis events and ultimately rewires various biological characteristics of neoplasm cells. In addition, irradiation damages subcellular structures, such as the cytoplasmic membrane, endoplasmic reticulum, ribosome, mitochondria, and lysosome of cancer cells to regulate various biological activities of tumor cells. Recent studies have shown that radiation can also change the tumor cell phenotype, immunogenicity and microenvironment, thereby globally altering the biological behavior of cancer cells. In this review, we focus on the effects of therapeutic radiation on the biological features of tumor cells to provide a theoretical basis for combinational therapy and inaugurate a new era in oncology.

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          Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.

          Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases. The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT. Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells. The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.
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            Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4.

            Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca(2+) flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).
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              Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen.

              The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell- and B cell-mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic.
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                Author and article information

                Contributors
                8610-87787652 , hlj-whj@163.com
                8610-87787652 , qianhaili001@163.com
                Journal
                Mil Med Res
                Mil Med Res
                Military Medical Research
                BioMed Central (London )
                2095-7467
                2054-9369
                30 June 2018
                30 June 2018
                2018
                : 5
                : 20
                Affiliations
                ISNI 0000 0000 9889 6335, GRID grid.413106.1, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, , Chinese Academy of Medical Sciences and Peking Union Medical College, ; RM6102, New Research Building, 17 Panjiayuan Nanli, Chaoyang District, 100021 Beijing China
                Article
                167
                10.1186/s40779-018-0167-4
                6026344
                29958545
                0702ce52-5b15-4122-a130-73c29030540a
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 November 2017
                : 13 June 2018
                Funding
                Funded by: CAMS Innovation Fund for Medical Sciences
                Award ID: No.2016-I2M-1-001
                Funded by: National Basic Research Program of China (973 Program)
                Award ID: No. 2015CB553904
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No. 81372158
                Award ID: No.81572842
                Funded by: National Natural Science Foundation of China (CN)
                Award ID: No.81372159
                Funded by: National Natural Science Foundation of China
                Award ID: No.81672459
                Funded by: Independent Issue of State Key Laboratory of Molecular Oncology
                Award ID: No. SKL-2017-16
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                radiation,cancer cells,biological features,combinational therapy

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