Opportunities and challenges of radiotherapy for treating cancer (original) (raw)

• Thariat, J., Hannoun-Levi, J. M., Sun Myint, A., Vuong, T. & Gerard, J. P. Past, present, and future of radiotherapy for the benefit of patients. Nat. Rev. Clin. Oncol. 10, 52–60 (2013).
  Article CAS PubMed Google Scholar
• Loeffler, J. S. & Durante, M. Charged particle therapy–optimization, challenges and future directions. Nat. Rev. Clin. Oncol. 10, 411–424 (2013).
  Article PubMed Google Scholar
• Lo, S. S. et al. Stereotactic body radiation therapy: a novel treatment modality. Nat. Rev. Clin. Oncol. 7, 44–54 (2010).
  Article PubMed Google Scholar
• Withers, H. R. The 4Rs of radiotherapy in Advances in Radiation Biology Vol. 5 (eds Lett, J. T. & Alder, H.) 241–249 (New York: Academic Press, 1975).
  Google Scholar
• Steel, G. G., McMillan, T. J. & Peacock, J. H. The 5Rs of radiobiology. Int. J. Radiat. Biol. 56, 1045–1048 (1989).
  Article CAS PubMed Google Scholar
• Good, J. S. & Harrington, K. J. The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clin. Oncol. (R. Coll. Radiol.) 25, 569–577 (2013).
  Article CAS Google Scholar
• Helleday, T., Petermann, E., Lundin, C., Hodgson, B. & Sharma, R. A. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 8, 193–204 (2008).
  Article CAS PubMed Google Scholar
• Chinnaiyan, P., Allen, G. W. & Harari, P. M. Radiation and new molecular agents, part II: targeting HDAC, HSP90, IGF-1R, PI3K, and Ras. Semin. Radiat. Oncol. 16, 59–64 (2006).
  Article PubMed Google Scholar
• Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Fuks, Z. & Kolesnick, R. Engaging the vascular component of the tumor response. Cancer Cell 8, 89–91 (2005).
  Article CAS PubMed Google Scholar
• Masterson, L. et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD010271 http://dx.doi.org/10.1002/14651858.CD010271.pub2 (2014).
  Google Scholar
• Lomax, M. E., Folkes, L. K. & O'Neill, P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin. Oncol. (R. Coll. Radiol.) 25, 578–585 (2013).
  Article CAS Google Scholar
• Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311 (1991).
  CAS PubMed Google Scholar
• Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).
  Article CAS PubMed Google Scholar
• Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Wang, X. et al. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol. Cell Biol. 27, 3098–3108 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Bekker-Jensen, S. & Mailand, N. Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair (Amst.) 9, 1219–1228 (2010).
  Article CAS Google Scholar
• Lieber, M. R. NHEJ and its backup pathways in chromosomal translocations. Nat. Struct. Mol. Biol. 17, 393–395 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Lieber, M. R. & Wilson, T. E. SnapShot: nonhomologous DNA end joining (NHEJ). Cell 142, 496–496.e1 (2010).
  Article CAS PubMed Google Scholar
• San Filippo, J., Sung, P. & Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008).
  Article CAS PubMed Google Scholar
• Onn, I., Heidinger-Pauli, J. M., Guacci, V., Unal, E. & Koshland, D. E. Sister chromatid cohesion: a simple concept with a complex reality. Annu. Rev. Cell Dev. Biol. 24, 105–129 (2008).
  Article CAS PubMed Google Scholar
• Maréchal, A. & Zou, L. RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response. Cell Res. 25, 9–23 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Moore, S., Stanley, F. K. & Goodarzi, A. A. The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation--no simple task. DNA Repair (Amst.) 17, 64–73 (2014).
  Article CAS Google Scholar
• Takahashi, A. et al. Nonhomologous end-joining repair plays a more important role than homologous recombination repair in defining radiosensitivity after exposure to high-LET radiation. Radiat. Res. 182, 338–344 (2014).
  Article CAS PubMed Google Scholar
• Averbeck, N. B. et al. DNA end resection is needed for the repair of complex lesions in G1-phase human cells. Cell Cycle 13, 2509–2516 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Durante, M. New challenges in high-energy particle radiobiology. Br. J. Radiol. 87, 20130626 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Nakajima, N. I. et al. Pre-exposure to ionizing radiation stimulates DNA double strand break end resection, promoting the use of homologous recombination repair. PLoS ONE 10, e0122582 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Shrivastav, M., De Haro, L. P. & Nickoloff, J. A. Regulation of DNA double-strand break repair pathway choice. Cell Res. 18, 134–147 (2008).
  Article CAS PubMed Google Scholar
• Hufnagl, A. et al. The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR. DNA Repair (Amst.) 27, 28–39 (2015).
  Article CAS Google Scholar
• Aylon, Y., Liefshitz, B. & Kupiec, M. The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J. 23, 4868–4875 (2004).
  Article PubMed PubMed Central CAS Google Scholar
• Hentges, P., Waller, H., Reis, C. C., Ferreira, M. G. & Doherty, A. J. Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1. Cell Rep. 9, 2011–2017 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Sorensen, C. S. et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat. Cell Biol. 7, 195–201 (2005).
  Article CAS PubMed Google Scholar
• Bryant, C., Scriven, K. & Massey, A. J. Inhibition of the checkpoint kinase Chk1 induces DNA damage and cell death in human leukemia and lymphoma cells. Mol. Cancer 13, 147 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Sears, C. R. & Turchi, J. J. Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways. J. Biol. Chem. 287, 24263–24272 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012).
  Article CAS PubMed Google Scholar
• Noel, G. et al. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol. Cancer Ther. 5, 564–574 (2006).
  Article CAS PubMed Google Scholar
• Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010).
  Article CAS PubMed Google Scholar
• Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
  Article CAS PubMed Google Scholar
• Koppensteiner, R. et al. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS ONE 9, e100041 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Wang, L. et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest. New Drugs 30, 2113–2120 (2012).
  Article CAS PubMed Google Scholar
• Reiss, K. A. et al. A phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis. Clin. Cancer Res. (2014).
• Chow, J. P. et al. PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy. Mol. Cancer Ther. 12, 2517–2528 (2013).
  Article CAS PubMed Google Scholar
• Nowsheen, S., Bonner, J. A. & Yang, E. S. The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy. Radiother. Oncol. 99, 331–338 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Chatterjee, P. et al. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2–ERG fusion gene-expressing and _PTEN_-deficient prostate cancer cells. PLoS ONE 8, e60408 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Castri, P. et al. Poly(ADP-ribose) polymerase-1 and its cleavage products differentially modulate cellular protection through NF-κB-dependent signaling. Biochim. Biophys. Acta 1843, 640–651 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Hunter, J. E. et al. NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699. Oncogene 31, 251–264 (2012).
  Article CAS PubMed Google Scholar
• Feng, F. Y. et al. Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer. Breast Cancer Res. Treat. 147, 81–94 (2014).
  Article CAS PubMed Google Scholar
• O'Shaughnessy, J. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364, 205–214 (2011).
  Article CAS PubMed Google Scholar
• Patel, A. G., De Lorenzo, S. B., Flatten, K. S., Poirier, G. G. & Kaufmann, S. H. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin. Cancer Res. 18, 1655–1662 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Morgan, M. A., Parsels, L. A., Maybaum, J. & Lawrence, T. S. Improving the efficacy of chemoradiation with targeted agents. Cancer Discov. 4, 280–291 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Takata, H. et al. Chromatin compaction protects genomic DNA from radiation damage. PLoS ONE 8, e75622 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Chapman, J. D. et al. Condensed chromatin and cell inactivation by single-hit kinetics. Radiat. Res. 151, 433–441 (1999).
  Article CAS PubMed Google Scholar
• Chiolo, I. et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732–744 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Storch, K. et al. Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Res. 70, 3925–3934 (2010).
  Article PubMed Google Scholar
• Jakob, B. et al. DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin. Nucleic Acids Res. 39, 6489–6499 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Chiolo, I., Tang, J., Georgescu, W. & Costes, S. V. Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin. Mutat. Res. 750, 56–66 (2013).
  Article CAS PubMed Google Scholar
• Jezkova, L. et al. Function of chromatin structure and dynamics in DNA damage, repair and misrepair: gamma-rays and protons in action. Appl. Radiat. Isot. 83 (Pt B), 128–136 (2014).
  Article CAS PubMed Google Scholar
• Falk, M., Lukasova, E. & Kozubek, S. Higher-order chromatin structure in DSB induction, repair and misrepair. Mutat. Res. 704, 88–100 (2010).
  Article CAS PubMed Google Scholar
• Frame, F. M. et al. HDAC inhibitor confers radiosensitivity to prostate stem-like cells. Br. J. Cancer 109, 3023–3033 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Pugh, J. L. et al. Histone deacetylation critically determines T cell subset radiosensitivity. J. Immunol. 193, 1451–1458 (2014).
  Article PubMed CAS Google Scholar
• Kruhlak, M. J., Celeste, A. & Nussenzweig, A. Monitoring DNA breaks in optically highlighted chromatin in living cells by laser scanning confocal microscopy. Methods Mol. Biol. 523, 125–140 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Becker, A., Durante, M., Taucher-Scholz, G. & Jakob, B. ATM alters the otherwise robust chromatin mobility at sites of DNA double-strand breaks (DSBs) in human cells. PLoS ONE 9, e92640 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Goodarzi, A. A., Jeggo, P. & Lobrich, M. The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax. DNA Repair (Amst.) 9, 1273–1282 (2010).
  Article CAS Google Scholar
• Goodarzi, A. A. & Jeggo, P. A. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. Int. J. Mol. Sci. 13, 11844–11860 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Iyengar, S. & Farnham, P. J. KAP1 protein: an enigmatic master regulator of the genome. J. Biol. Chem. 286, 26267–26276 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Lee, D. H. et al. Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response. EMBO J. 31, 2403–2415 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Dimitrova, N., Chen, Y. C., Spector, D. L. & de Lange, T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456, 524–528 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Averbeck, N. B. & Durante, M. Protein acetylation within the cellular response to radiation. J. Cell Physiol. 226, 962–967 (2011).
  Article CAS PubMed Google Scholar
• Rosato, R. R. & Grant, S. Histone deacetylase inhibitors in cancer therapy. Cancer Biol. Ther. 2, 30–37 (2003).
  Article PubMed Google Scholar
• Zhang, L. et al. Recent progress in the development of histone deacetylase inhibitors as anti-cancer agents. Mini Rev. Med. Chem. 13, 1999–2013 (2013).
  Article CAS PubMed Google Scholar
• Camphausen, K. et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int. J. Cancer 114, 380–386 (2005).
  Article CAS PubMed Google Scholar
• Cerna, D., Camphausen, K. & Tofilon, P. J. Histone deacetylation as a target for radiosensitization. Curr. Top. Dev. Biol. 73, 173–204 (2006).
  Article CAS PubMed Google Scholar
• Shabason, J. E., Tofilon, P. J. & Camphausen, K. HDAC inhibitors in cancer care. Oncology (Williston Park) 24, 180–185 (2010).
  Google Scholar
• Jung, M. et al. Novel HDAC inhibitors with radiosensitizing properties. Radiat. Res. 163, 488–493 (2005).
  Article CAS PubMed Google Scholar
• Konsoula, Z., Velena, A., Lee, R., Dritschilo, A. & Jung, M. Histone deacetylase inhibitor: antineoplastic agent and radiation modulator. Adv. Exp. Med. Biol. 720, 171–179 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Chinnaiyan, P. et al. Postradiation sensitization of the histone deacetylase inhibitor valproic acid. Clin. Cancer Res. 14, 5410–5415 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Karagiannis, T. C., Kn, H. & El-Osta, A. The epigenetic modifier, valproic acid, enhances radiation sensitivity. Epigenetics 1, 131–137 (2006).
  Article PubMed Google Scholar
• Noguchi, H. et al. Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery. Endocr. J. 56, 245–249 (2009).
  Article PubMed Google Scholar
• Ree, A. H. et al. Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol. 11, 459–464 (2010).
  Article CAS PubMed Google Scholar
• Chen, H. P., Zhao, Y. T. & Zhao, T. C. Histone deacetylases and mechanisms of regulation of gene expression. Crit. Rev. Oncog. 20, 35–47 (2015).
  Article PubMed PubMed Central Google Scholar
• Ren, J. et al. HDAC as a therapeutic target for treatment of endometrial cancers. Curr. Pharm. Des. 20, 1847–1856 (2014).
  Article CAS PubMed Google Scholar
• Nakajima, S. & Kitamura, M. Bidirectional regulation of NF-κB by reactive oxygen species: a role of unfolded protein response. Free Radic. Biol. Med. 65, 162–174 (2013).
  Article CAS PubMed Google Scholar
• Yoon, J. Y., Ishdorj, G., Graham, B. A., Johnston, J. B. & Gibson, S. B. Valproic acid enhances fludarabine-induced apoptosis mediated by ROS and involving decreased AKT and ATM activation in B-cell-lymphoid neoplastic cells. Apoptosis 19, 191–200 (2014).
  Article CAS PubMed Google Scholar
• Jeong, S. G. & Cho, G. W. Trichostatin a modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow-mesenchymal stem cells. Cell Biochem. Funct. 33, 37–43 (2014).
  Article CAS PubMed Google Scholar
• Park, S. et al. Suberoylanilide hydroxamic acid induces ROS-mediated cleavage of HSP90 in leukemia cells. Cell Stress Chaperones 20, 149–157 (2015).
  Article CAS PubMed Google Scholar
• Wolf, I. M. et al. Histone deacetylases inhibition by SAHA/vorinostat normalizes the glioma microenvironment via xCT equilibration. Sci. Rep. 4, 6226 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Sholler, G. S. et al. PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. J. Cancer Ther. Res. 2, 21 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
  Article CAS PubMed Google Scholar
• Wang, H. et al. The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair (Amst.) 11, 146–156 (2012).
  Article CAS Google Scholar
• Blattmann, C. et al. Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int. J. Radiat. Oncol. Biol. Phys. 78, 237–245 (2010).
  Article CAS PubMed Google Scholar
• Kachhap, S. K. et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS ONE 5, e11208 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Ren, J. et al. Epigenetic interventions increase the radiation sensitivity of cancer cells. Curr. Pharm. Des. 20, 1857–1865 (2014).
  Article CAS PubMed Google Scholar
• Brown, S. L., Kolozsvary, A., Liu, J., Ryu, S. & Kim, J. H. Histone deacetylase inhibitors protect against and mitigate the lethality of total-body irradiation in mice. Radiat. Res. 169, 474–478 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Grabiec, A. M., Tak, P. P. & Reedquist, K. A. Function of histone deacetylase inhibitors in inflammation. Crit. Rev. Immunol. 31, 233–263 (2011).
  Article CAS PubMed Google Scholar
• Kim, H. J. & Chuang, D. M. HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am. J. Transl. Res. 6, 206–223 (2014).
  PubMed PubMed Central Google Scholar
• Felice, C., Lewis, A., Armuzzi, A., Lindsay, J. O. & Silver, A. Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment. Pharmacol. Ther. 41, 26–38 (2015).
  Article CAS PubMed Google Scholar
• Morris, Z. S. & Harari, P. M. Interaction of radiation therapy with molecular targeted agents. J. Clin. Oncol. 32, 2886–2893 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, D. J. & Nirodi, C. S. The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clin. Cancer Res. 13, 6555–6560 (2007).
  Article CAS PubMed Google Scholar
• Kim, K. et al. Epidermal growth factor receptor vIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation. Mol. Cancer Res. 6, 426–434 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Baumann, M. et al. EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother. Oncol. 83, 238–248 (2007).
  Article CAS PubMed Google Scholar
• Bonner, J. A. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567–578 (2006).
  Article CAS PubMed Google Scholar
• Bonner, J. A. et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11, 21–28 (2010).
  Article CAS PubMed Google Scholar
• Ang, K. K. et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J. Clin. Oncol. 32, 2940–2950 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Debucquoy, A., Machiels, J. P., McBride, W. H. & Haustermans, K. Integration of epidermal growth factor receptor inhibitors with preoperative chemoradiation. Clin. Cancer Res. 16, 2709–2714 (2010).
  Article CAS PubMed Google Scholar
• Kriegs, M. et al. Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest. Radiother. Oncol. http://dx.doi.org/10.1016/j.radonc.2015.02.018 (2015).
• Dent, P. et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat. Res. 159, 283–300 (2003).
  Article CAS PubMed Google Scholar
• Liccardi, G., Hartley, J. A. & Hochhauser, D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 71, 1103–1114 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Knebel, A., Rahmsdorf, H. J., Ullrich, A. & Herrlich, P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J. 15, 5314–5325 (1996).
  Article PubMed PubMed Central CAS Google Scholar
• Schmidt-Ullrich, R. K. et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15, 1191–1197 (1997).
  Article CAS PubMed Google Scholar
• Kim, J., Adam, R. M. & Freeman, M. R. Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Res. 65, 8242–8249 (2005).
  Article CAS PubMed Google Scholar
• Kefaloyianni, E., Gaitanaki, C. & Beis, I. ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-κB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 18, 2238–2251 (2006).
  Article CAS PubMed Google Scholar
• Papaiahgari, S., Zhang, Q., Kleeberger, S. R., Cho, H. Y. & Reddy, S. P. Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS–EGFR–PI3K–Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid. Redox Signal. 8, 43–52 (2006).
  Article CAS PubMed Google Scholar
• Han, W. & Lo, H. W. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 318, 124–134 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Dittmann, K. et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J. Biol. Chem. 280, 31182–31189 (2005).
  Article CAS PubMed Google Scholar
• Dittmann, K., Mayer, C. & Rodemann, H. P. Nuclear EGFR as novel therapeutic target: insights into nuclear translocation and function. Strahlenther. Onkol. 186, 1–6 (2010).
  Article PubMed Google Scholar
• Liccardi, G., Hartley, J. A. & Hochhauser, D. Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage. Clin. Cancer Res. 20, 3496–3506 (2014).
  Article CAS PubMed Google Scholar
• Javvadi, P. et al. Threonine 2609 phosphorylation of the DNA-dependent protein kinase is a critical prerequisite for epidermal growth factor receptor-mediated radiation resistance. Mol. Cancer Res. 10, 1359–1368 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Kim, I. A. et al. Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6. Radiother. Oncol. 92, 125–132 (2009).
  Article CAS PubMed Google Scholar
• Dittmann, K., Mayer, C., Rodemann, H. P. & Huber, S. M. EGFR cooperates with glucose transporter SGLT1 to enable chromatin remodeling in response to ionizing radiation. Radiother. Oncol. 107, 247–251 (2013).
  Article CAS PubMed Google Scholar
• Dittmann, K. et al. Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access. Radiother. Oncol. 99, 317–322 (2011).
  Article CAS PubMed Google Scholar
• Vlashi, E., McBride, W. H. & Pajonk, F. Radiation responses of cancer stem cells. J. Cell Biochem. 108, 339–342 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Vlashi, E. & Pajonk, F. Targeted cancer stem cell therapies start with proper identification of the target. Mol. Cancer Res. 8, 291 (2010).
  Article PubMed PubMed Central Google Scholar
• Phillips, T. M., McBride, W. H. & Pajonk, F. The response of CD24−/low/CD44+ breast cancer-initiating cells to radiation. J. Natl Cancer Inst. 98, 1777–1785 (2006).
  Article PubMed Google Scholar
• Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
  Article CAS PubMed Google Scholar
• Woodward, W. A. et al. WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc. Natl Acad. Sci. USA 104, 618–623 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, Y., Joo, K. M., Jin, J. & Nam, D. H. Cancer stem cells and their mechanism of chemo-radiation resistance. Int. J. Stem Cells 2, 109–114 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Rich, J. N. Cancer stem cells in radiation resistance. Cancer Res. 67, 8980–8984 (2007).
  Article CAS PubMed Google Scholar
• Bourguignon, L. Y., Shiina, M. & Li, J. J. Hyaluronan–CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. Adv. Cancer Res. 123, 255–275 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• McCord, A. M., Jamal, M., Williams, E. S., Camphausen, K. & Tofilon, P. J. CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin. Cancer Res. 15, 5145–5153 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Zielske, S. P., Spalding, A. C., Wicha, M. S. & Lawrence, T. S. Ablation of breast cancer stem cells with radiation. Transl. Oncol. 4, 227–233 (2011).
  Article PubMed PubMed Central Google Scholar
• Vlashi, E. et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc. Natl Acad. Sci. USA 108, 16062–16067 (2011).
  Article PubMed PubMed Central Google Scholar
• Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Zafarana, G. & Bristow, R. G. Tumor senescence and radioresistant tumor-initiating cells (TICs): let sleeping dogs lie! Breast Cancer Res. 12, 111 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Dong, Q. et al. Radioprotective effects of BMI-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. J. Invest. Dermatol. 131, 1216–1225 (2011).
  Article CAS PubMed Google Scholar
• Pignalosa, D. & Durante, M. Overcoming resistance of cancer stem cells. Lancet Oncol. 13, e187–e188 (2012).
  Article PubMed Google Scholar
• Chen, T. et al. Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity. Chin. J Cancer 29, 270–276 (2010).
  Article PubMed Google Scholar
• Vlashi, E. & Pajonk, F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin. Cancer Biol. 31, 28–35 (2015).
  Article CAS PubMed Google Scholar
• Lagadec, C., Vlashi, E., Della Donna, L., Dekmezian, C. & Pajonk, F. Radiation-induced reprogramming of breast cancer cells. Stem Cells 30, 833–844 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Shoshani, O. & Zipori, D. Stress as a fundamental theme in cell plasticity. Biochim. Biophys. Acta 1849, 371–377 (2015).
  Article CAS PubMed Google Scholar
• Chlon, T. M. et al. High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells. J. Virol. 88, 11315–11326 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Gomez-Casal, R. et al. Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Mol. Cancer 12, 94 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Patel, S. S., Shah, K. A., Shah, M. J., Kothari, K. C. & Rawal, R. M. Cancer stem cells and stemness markers in oral squamous cell carcinomas. Asian Pac. J. Cancer Prev. 15, 8549–8556 (2014).
  Article PubMed Google Scholar
• Venere, M. et al. Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 21, 258–269 (2014).
  Article CAS PubMed Google Scholar
• Gilabert, M. et al. Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS ONE 9, e104302 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Yoshikawa, M. et al. xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res. 73, 1855–1866 (2013).
  Article CAS PubMed Google Scholar
• Greenow, K. & Clarke, A. R. Controlling the stem cell compartment and regeneration in vivo: the role of pluripotency pathways. Physiol. Rev. 92, 75–99 (2012).
  Article CAS PubMed Google Scholar
• Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2015.61 (2015).
• Mizugaki, H. et al. γ-secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer. Br. J. Cancer 106, 1953–1959 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Lin, J., Zhang, X. M., Yang, J. C., Ye, Y. B. & Luo, S. Q. γ-secretase inhibitor-I enhances radiosensitivity of glioblastoma cell lines by depleting CD133+ tumor cells. Arch. Med. Res. 41, 519–529 (2010).
  Article CAS PubMed Google Scholar
• Lagadec, C. et al. Radiation-induced Notch signaling in breast cancer stem cells. Int. J. Radiat. Oncol. Biol. Phys. 87, 609–618 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Diaz-Padilla, I. et al. A phase Ib combination study of RO4929097, a γ-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest. New Drugs 31, 1182–1191 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• De Strooper, B. & Chavez Gutierrez, L. Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer disease and beyond. Annu. Rev. Pharmacol. Toxicol. 55, 419–437 (2015).
  Article CAS PubMed Google Scholar
• Kim, S. H., Kim, J. H. & Fried, J. Enhancement of the radiation response of cultured tumor cells by chloroquine. Cancer 32, 536–540 (1973).
  Article CAS PubMed Google Scholar
• Firat, E., Weyerbrock, A., Gaedicke, S., Grosu, A. L. & Niedermann, G. Chloroquine or chloroquine–PI3K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem-like glioma cells. PLoS ONE 7, e47357 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Maycotte, P. & Thorburn, A. Targeting autophagy in breast cancer. World J. Clin. Oncol. 5, 224–240 (2014).
  Article PubMed PubMed Central Google Scholar
• Ratikan, J. A., Sayre, J. W. & Schaue, D. Chloroquine engages the immune system to eradicate irradiated breast tumors in mice. Int. J. Radiat. Oncol. Biol. Phys. 87, 761–768 (2013).
  Article CAS PubMed Google Scholar
• Balic, A. et al. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Mol. Cancer Ther. 13, 1758–1771 (2014).
  Article CAS PubMed Google Scholar
• Xiao, W. et al. CD44 is a biomarker associated with human prostate cancer radiation sensitivity. Clin. Exp. Metastasis 29, 1–9 (2012).
  Article CAS PubMed Google Scholar
• Ni, J. et al. CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance. Prostate 74, 602–617 (2014).
  Article CAS PubMed Google Scholar
• Timmerman, L. A. et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450–465 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Wang, F. & Yang, Y. Suppression of the xCT–CD44v antiporter system sensitizes triple-negative breast cancer cells to doxorubicin. Breast Cancer Res. Treat. 147, 203–210 (2014).
  Article CAS PubMed Google Scholar
• Takeuchi, S. et al. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma. Neurol. India 62, 42–47 (2014).
  Article PubMed Google Scholar
• McDonald, J. T. et al. Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res. 70, 8886–8895 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Bauer, A. K., Hill, T. 3rd & Alexander, C. M. The involvement of NRF2 in lung cancer. Oxid. Med. Cell Longev. 2013, 746432 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Hast, B. E. et al. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res. 74, 808–817 (2014).
  Article CAS PubMed Google Scholar
• Tao, S. et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 74, 7430–7441 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med. 49, 1603–1616 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199–218 (2014).
  Article CAS PubMed Google Scholar
• Buettner, G. R., Wagner, B. A. & Rodgers, V. G. Quantitative redox biology: an approach to understand the role of reactive species in defining the cellular redox environment. Cell Biochem. Biophys. 67, 477–483 (2013).
  Article CAS PubMed Google Scholar
• Ma, T. et al. Dual-functional probes for sequential thiol and redox homeostasis sensing in live cells. Analyst 140, 322–329 (2015).
  Article CAS PubMed Google Scholar
• Kruger, A. & Ralser, M. ATM is a redox sensor linking genome stability and carbon metabolism. Sci. Signal. 4, pe17 (2011).
  Article CAS PubMed Google Scholar
• Perry, J. J. & Tainer, J. A. All stressed out without ATM kinase. Sci. Signal. 4, pe18 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Shirwany, N. A. & Zou, M. H. AMPK: a cellular metabolic and redox sensor. A minireview. Front. Biosci. (Landmark Ed.) 19, 447–474 (2014).
  Article CAS Google Scholar
• McBride, W. H. et al. A sense of danger from radiation. Radiat. Res. 162, 1–19 (2004).
  Article CAS PubMed Google Scholar
• Vazquez-Martin, A. et al. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist. Updat. 14, 212–223 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Najbauer, J., Kraljik, N. & Nemeth, P. Glioma stem cells: markers, hallmarks and therapeutic targeting by metformin. Pathol. Oncol. Res. 20, 789–797 (2014).
  Article CAS PubMed Google Scholar
• Skinner, H. D. et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med. 2, 99–107 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Spratt, D. E. et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur. Urol. 63, 709–716 (2013).
  Article CAS PubMed Google Scholar
• Skinner, H. D. et al. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. 52, 1002–1009 (2013).
  Article CAS PubMed Google Scholar
• Ferro, A. et al. Evaluation of diabetic patients with breast cancer treated with metformin during adjuvant radiotherapy. Int. J. Breast Cancer 2013, 659723 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Eckers, J. C., Kalen, A. L., Xiao, W., Sarsour, E. H. & Goswami, P. C. Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury. Int. J. Radiat. Oncol. Biol. Phys. 87, 619–625 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Gao, Z. et al. Late ROS accumulation and radiosensitivity in SOD1-overexpressing human glioma cells. Free Radic. Biol. Med. 45, 1501–1509 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Le, O. N. et al. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9, 398–409 (2010).
  Article PubMed CAS Google Scholar
• Sabin, R. J. & Anderson, R. M. Cellular Senescence—its role in cancer and the response to ionizing radiation. Genome Integr. 2, 7 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).
  Article CAS PubMed Google Scholar
• Durante, M., Reppingen, N. & Held, K. D. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol. Med. 19, 565–582 (2013).
  Article CAS PubMed Google Scholar
• Coppe, J. P. et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Westbrook, A. M. et al. The role of tumour necrosis factor-alpha and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity. Mutagenesis 27, 77–86 (2012).
  Article CAS PubMed Google Scholar
• Schaue, D. & McBride, W. H. Links between innate immunity and normal tissue radiobiology. Radiation Res. 173, 406–417 (2010).
  Article CAS PubMed Google Scholar
• Kansara, M. et al. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J. Clin. Invest. 123, 5351–5360 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Klammer, H., Mladenov, E., Li, F. & Iliakis, G. Bystander effects as manifestation of intercellular communication of DNA damage and of the cellular oxidative status. Cancer Lett. 356, 58–71 (2015).
  Article CAS PubMed Google Scholar
• Kim, K. et al. High throughput screening of small molecule libraries for modifiers of radiation responses. Int. J. Radiat. Biol. 87, 839–845 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Demaria, S., Bhardwaj, N., McBride, W. H. & Formenti, S. C. Combining radiotherapy and immunotherapy: a revived partnership. Int. J. Radiat. Oncol. Biol. Phys. 63, 655–666 (2005).
  Article PubMed PubMed Central Google Scholar
• Formenti, S. C. & Demaria, S. Radiation therapy to convert the tumor into an in situ vaccine. Int. J. Radiat. Oncol. Biol. Phys. 84, 879–880 (2012).
  Article PubMed Google Scholar
• Schaue, D., Ratikan, J. A., Iwamoto, K. S. & McBride, W. H. Maximizing tumor immunity with fractionated radiation. Int. J. Radiat. Oncol. Biol. Phys. 83, 1306–1310 (2012).
  Article CAS PubMed Google Scholar
• Schaue, D. et al. T-cell responses to survivin in cancer patients undergoing radiation therapy. Clin. Cancer Res. 14, 4883–4890 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Liao, Y.-P., Meng, W. S. & McBride, W. H. Antigen presentation by dendritic cells is affected after irradiation [abstract]. Proc. Am. Assoc. Cancer Res. 43, 480–481 (2002).
  Google Scholar
• Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Butterfield, L. H. et al. Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin. Cancer Res. 9, 998–1008 (2003).
  CAS PubMed Google Scholar
• Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).
  Article CAS PubMed Google Scholar
• Mullen, C. A., Coale, M. M., Lowe, R. & Blaese, R. M. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 54, 1503–1506 (1994).
  CAS PubMed Google Scholar
• Pizova, K. et al. Photodynamic therapy for enhancing antitumour immunity. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 156, 93–102 (2012).
  Article CAS PubMed Google Scholar
• Chen, F. H. et al. Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clin. Cancer Res. 15, 1721–1729 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• McBride, W. H. Phenotype and functions of intratumoral macrophages. Biochim. Biophys. Acta 865, 27–41 (1986).
  CAS PubMed Google Scholar
• Gajewski, T. F. et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr. Opin. Immunol. 25, 268–276 (2013).
  Article CAS PubMed Google Scholar
• Dougherty, G. J. & McBride, W. H. Immunoregulating activity of tumor-associated macrophages. Cancer Immunol. Immunother. 23, 67–72 (1986).
  Article CAS PubMed Google Scholar
• Kikuchi, N. et al. Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and TH1/TH2 balance. Respir. Res. 11, 31 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Rockwell, C. E., Zhang, M., Fields, P. E. & Klaassen, C. D. TH2 skewing by activation of Nrf2 in CD4+ T cells. J. Immunol. 188, 1630–1637 (2012).
  Article PubMed CAS Google Scholar
• Schaue, D., Xie, M. W., Ratikan, J. A. & McBride, W. H. Regulatory T cells in radiotherapeutic responses. Front. Oncol. 2, 90 (2012).
  PubMed PubMed Central CAS Google Scholar
• Tsai, C. S. et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-1 and COX-2, and promote tumor growth. Int. J. Radiat. Oncol. Biol. Phys. 68, 499–507 (2007).
  Article CAS PubMed Google Scholar
• Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Tseng, D., Vasquez-Medrano, D. A. & Brown, J. M. Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br. J. Cancer 104, 1805–1809 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, F. H. et al. Combination of vessel-targeting agents and fractionated radiation therapy: the role of the SDF-1/CXCR4 pathway. Int. J. Radiat. Oncol. Biol. Phys. 86, 777–784 (2013).
  Article PubMed Google Scholar
• Brown, J. M. Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br. J. Radiol. 87, 20130686 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Xu, J. et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782–2794 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Chiang, C. S. et al. Irradiation promotes an M2 macrophage phenotype in tumor hypoxia. Front. Oncol. 2, 89 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Ahn, G. O. & Brown, J. M. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle 8, 970–976 (2009).
  Article PubMed CAS Google Scholar
• Mantovani, A. & Allavena, P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med. 212, 435–445 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Tsai, J. H. et al. Ionizing radiation inhibits tumor neovascularization by inducing ineffective angiogenesis. Cancer Biol. Ther. 4, 1395–1400 (2005).
  Article CAS PubMed Google Scholar
• Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Johnson, D. B., Rioth, M. J. & Horn, L. Immune checkpoint inhibitors in NSCLC. Curr. Treat. Options Oncol. 15, 658–669 (2014).
  Article PubMed PubMed Central Google Scholar
• Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).
  CAS PubMed Google Scholar
• Pilones, K. A., Vanpouille-Box, C. & Demaria, S. Combination of radiotherapy and immune checkpoint inhibitors. Semin. Radiat. Oncol. 25, 28–33 (2015).
  Article PubMed Google Scholar
• Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Stamell, E. F., Wolchok, J. D., Gnjatic, S., Lee, N. Y. & Brownell, I. The abscopal effect associated with a systemic anti-melanoma immune response. Int. J. Radiat. Oncol. Biol. Phys. 85, 293–295 (2013).
  Article PubMed Google Scholar
• Hiniker, S. M. et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl. Oncol. 5, 404–407 (2012).
  Article PubMed PubMed Central Google Scholar
• Postow, M. A., Harding, J. & Wolchok, J. D. Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. Cancer J. 18, 153–159 (2012).
  Article PubMed PubMed Central CAS Google Scholar