Radioresponse is influenced by factors apart from the targeted cancer cells; in fact, endothelial cells and infiltrating immune cells within the tumor microenvironment (TME) are the two main components affecting the outcome of radiotherapy. The benefits of fractionated radiotherapy are attenuated through the upregulation of hypoxia inducible factor-1α and vascular endothelial growth factor. The therapeutic effect of antiangiogenic agents is counteracted by the mobilization of endogenous proangiogenic cells to the TME. This study highlights the importance of radiation timing within a vascular normalization window and discusses the importance of immune cells that comprise the microenvironment. A balance between favorable tumor-infiltrating immune cells, including cytotoxic T cells, natural killer cells, and dendritic cells, and the unfavorable cells, such as tumor-associated macrophages and regulatory T cells, determines the final tumor-control probability. The reciprocal complementation between combinations of radiotherapy and immunotherapy strategies through modulation of the tumor immunological microenvironment may yield promising results in the future.
Get full access to this article
View all access options for this article.
References
1.
ShinoharaET, MaityA. Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment. Curr Mol Med, 2009; 9:1034.
2.
AhnGO, BrownJM. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: Experimental models and clinical perspectives. Cell Cycle, 2009; 8:970.
3.
Garcia-BarrosM, ParisF, Cordon-CardoCet al.Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 2003; 300:1155.
ZengL, OuG, ItasakaSet al.TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis. Cancer Sci, 2008; 99:2327.
6.
KolesnickR, FuksZ. Radiation and ceramide-induced apoptosis. Oncogene, 2003; 22:5897.
7.
LinX, FuksZ, KolesnickR. Ceramide mediates radiation-induced death of endothelium. Crit Care Med, 2000; 28:N87.
8.
FuksZ, KolesnickR. Engaging the vascular component of the tumor response. Cancer Cell, 2005; 8:89.
9.
MoellerBJ, CaoY, LiCYet al.Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell, 2004; 5:429.
10.
KoukourakisMI, GiatromanolakiA, SheldonHet al.Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: Vasculature-independent radiosensitizing effect of bevacizumab. Clin Cancer Res, 2009; 15:7069.
11.
AndreN, PadovaniL, PasquierE. Metronomic scheduling of anticancer treatment: The next generation of multitarget therapy?Future Oncol, 2011; 7:385.
12.
SenanS, SmitEF. Design of clinical trials of radiation combined with antiangiogenic therapy. Oncologist, 2007; 12:465.
13.
WillettCG, BoucherY, di TomasoEet al.Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med, 2004; 10:145.
14.
LogesS, MazzoneM, HohensinnerPet al.Silencing or fueling metastasis with VEGF inhibitors: Antiangiogenesis revisited. Cancer Cell, 2009; 15:167.
15.
SorensenAG, BatchelorTT, ZhangW-Tet al.A “Vascular Normalization Index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res, 2009; 69:5296.
16.
BatchelorTT, SorensenAG, di TomasoEet al.AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell, 2007; 11:83.
17.
DingsRP, LorenM, HeunHet al.Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res, 2007; 13:3395.
18.
ChiKH, LiaoCS, ChangCCet al.Angiogenic blockade and radiotherapy in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys, 2010; 78:188.
19.
BonnerJA, HarariPM, GiraltJet al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med, 2006; 354:567.
20.
NyatiMK, MorganMA, FengFYet al.Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer, 2006; 6:876.
21.
CernigliaGJ, PoreN, TsaiJHet al.Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy. PLoS One, 2009; 4:e6539.
22.
Lopez-AlbaiteroA, LeeSC, MorganSet al.Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother, 2009; 58:1853.
23.
BozecA, SudakaA, FischelJLet al.Combined effects of bevacizumab with erlotinib and irradiation: A preclinical study on a head and neck cancer orthotopic model. Br J Cancer, 2008; 99:93.
24.
BozecA, SudakaA, ToussanNet al.Combination of sunitinib, cetuximab and irradiation in an orthotopic head and neck cancer model. Ann Oncol, 2009; 20:1703.
ChangCC, ChiKH, KaoSJet al.Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: A mono-institutional experience. Lung Cancer, 2011; 73:189.
27.
JungIL, KangHJ, KimKCet al.PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer. Int J Mol Med, 2010; 25:517.
28.
LeeYS, OhJ-H, YoonSet al.Differential gene expression profiles of radioresistant non-small-cell lung cancer cell lines established by fractionated irradiation: Tumor protein p53-inducible protein 3 confers sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys, 2010; 77:858.
29.
ShimojiH, MiyazatoH, NakachiAet al.Expression of p53, bcl-2, and bax as predictors of response to radiotherapy in esophageal cancer. Dis Esophagus, 2000; 13:185.
30.
PanJ-J, ZhangS-W, ChenC-Bet al.Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol, 2009; 27:799.
KnoopsL, HaasR, de KempSet al.In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma. Blood, 2007; 110:1116.
33.
XueW, ZenderL, MiethingCet al.Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 2007; 445:656.
34.
GasserS, OrsulicS, BrownEJet al.The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature, 2005; 436:1186.
35.
DisisML. Immune regulation of cancer. J Clin Oncol, 2010; 28:4531.
36.
PagesF, GalonJ, Dieu-NosjeanMCet al.Immune infiltration in human tumors: A prognostic factor that should not be ignored. Oncogene, 2009; 29:1093.
37.
ZhangL, Conejo-GarciaJR, KatsarosDet al.Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med, 2003; 348:203.
38.
PagesF, GalonJ, FridmanWH. The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol, 2008; 84:981.
39.
RauletDH, GuerraN. Oncogenic stress sensed by the immune system: Role of natural killer cell receptors. Nat Rev Immunol, 2009; 9:568.
40.
ZitvogelL, KeppO, KroemerG. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol, 2011; 8:151.
41.
ApetohL, GhiringhelliF, TesniereAet al.The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev, 2007; 220:47.
42.
ApetohL, GhiringhelliF, TesniereAet al.Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med, 2007; 13:1050.
43.
de VisserKE, EichtenA, CoussensLM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer, 2006; 6:24.
RakhraK, BachireddyP, ZabuawalaTet al.CD4+ T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell, 2010; 18:485.
Diaz-MonteroCM, SalemML, NishimuraMIet al.Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother, 2009; 58:49.
48.
GabrilovichDI, NagarajS. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 2009; 9:162.
49.
KoJS, RaymanP, IrelandJet al.Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res, 2010; 70:3526.
50.
MasonKA, ArigaH, NealRet al.Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy. Clin Cancer Res, 2005; 11:361.
51.
ChiCH, WangYS, YangCHet al.Neoadjuvant immunotherapy enhances radiosensitivity through natural killer cell activation. Cancer Biother Radiopharm, 2010; 25:39.
52.
ZwirnerNW, CrociDO, DomaicaCIet al.Overcoming the hurdles of tumor immunity by targeting regulatory pathways in innate and adaptive immune cells. Curr Pharm Des, 2010; 16:255.
53.
DemariaS, VolmMD, ShapiroRLet al.Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res, 2001; 7:3025.
54.
SchaueD, Comin-AnduixB, RibasAet al.T-cell responses to survivin in cancer patients undergoing radiation therapy. Clin Cancer Res, 2008; 14:4883.
55.
ApetohL, TesniereA, GhiringhelliFet al.Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res, 2008; 68:4026.
56.
KarnoubAE, DashAB, VoAPet al.Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 2007; 449:557.
57.
MashkaniB, GriffithR, AshmanLK. Colony stimulating factor-1 receptor as a target for small molecule inhibitors. Bioorg Med Chem, 2010; 18:1789.
58.
Ozao-ChoyJ, MaG, KaoJet al.The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res, 2009; 69:2514.
59.
OnishiT, HayashiN, TheriaultRLet al.Future directions of bone-targeted therapy for metastatic breast cancer. Nat Rev Clin Oncol, 2010; 7:641.
60.
CatenaR, Luis-RaveloD, AntonIet al.PDGFR signaling blockade in marrow stroma impairs lung cancer bone metastasis. Cancer Res, 2011; 71:164.
61.
ZhangW, ZhuXD, SunHCet al.Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res, 2010; 16:3420.
62.
MelaniC, SangalettiS, BarazzettaFMet al.Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res, 2007; 67:11438.
63.
ShiraishiK, IshiwataY, NakagawaKet al.Enhancement of antitumor radiation efficacy and consistent induction of the abscopal effect in mice by ECI301, an active variant of macrophage inflammatory protein-1alpha. Clin Cancer Res, 2008; 14:1159.
64.
Teitz-TennenbaumS, LiQ, OkuyamaRet al.Mechanisms involved in radiation enhancement of intratumoral dendritic cell therapy. J Immunother, 2008; 31:345.
65.
ChiKH, LiuSJ, LiCPet al.Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother, 2005; 28:129.
