IFN-γ Mediates the Antitumor Effects of Radiation Therapy in a Murine Colon Tumor

Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interestingly, IR therapy had no effect on tumor burden in IFNγKO mice. We further determined that intratumoral levels of IFN-γ increased 2 days following IR, which directly correlated with a decrease in tumor burden that was not a result of direct cytotoxic effects of IFN-γ on tumor cells. T cells from IR-treated tumors exhibited a far greater capacity to lyse tumor cells in a 51Cr release assay, a process that was dependent on IFN-γ. CD8+ T cells were the predominant producers of IFN-γ, as demonstrated by IFN-γ intracellular staining and studies in IFN-γ reporter mice. Elimination of CD8+ T cells by antibody treatment reduced the intratumoral levels of IFN-γ by over 90%. More importantly, elimination of CD8+ T cells completely abrogated the effects of radiation therapy. Our data suggest that IFN-γ plays a pivotal role in mediating the antitumor effects of IR therapy. Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interestingly, IR therapy had no effect on tumor burden in IFNγKO mice. We further determined that intratumoral levels of IFN-γ increased 2 days following IR, which directly correlated with a decrease in tumor burden that was not a result of direct cytotoxic effects of IFN-γ on tumor cells. T cells from IR-treated tumors exhibited a far greater capacity to lyse tumor cells in a 51Cr release assay, a process that was dependent on IFN-γ. CD8+ T cells were the predominant producers of IFN-γ, as demonstrated by IFN-γ intracellular staining and studies in IFN-γ reporter mice. Elimination of CD8+ T cells by antibody treatment reduced the intratumoral levels of IFN-γ by over 90%. More importantly, elimination of CD8+ T cells completely abrogated the effects of radiation therapy. Our data suggest that IFN-γ plays a pivotal role in mediating the antitumor effects of IR therapy. Historically, ionizing radiation (IR) therapy was thought to control cancer predominantly by inducing tumor cell death through DNA damage. However, a new paradigm is emerging, strongly suggesting that the immune system mediates many of the antitumor effects of radiotherapy. Our laboratory has previously demonstrated that local radiation therapy in a melanoma mouse model results in tumor cell death, facilitating the release of tumor antigen.1Lugade A.A. Moran J.P. Gerber S.A. Rose R.C. Frelinger J.G. Lord E.M. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor.J Immunol. 2005; 174: 7516-7523Crossref PubMed Scopus (761) Google Scholar Freed antigen can be processed by antigen-presenting cells and used to stimulate effector cells within the draining lymph node. Consequently, these effector cells were able to traffic to the tumor where they could recognize and lyse malignant cells, thereby reducing tumor growth. Additional reports have supported the concept that the immune system is pivotal in determining the effectiveness of radiation therapy.2Apetoh L. Ghiringhelli F. Tesniere A. Obeid M. Ortiz C. Criollo A. Mignot G. Maiuri M.C. Ullrich E. Saulnier P. Yang H. Amigorena S. Ryffel B. Barrat F.J. Saftig P. Levi F. Lidereau R. Nogues C. Mira J.P. Chompret A. Joulin V. Clavel-Chapelon F. Bourhis J. Andre F. Delaloge S. Tursz T. Kroemer G. Zitvogel L. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.Nat Med. 2007; 13: 1050-1059Crossref PubMed Scopus (2473) Google Scholar, 3Lee Y. Auh S.L. Wang Y. Burnette B. Meng Y. Beckett M. Sharma R. Chin R. Tu T. Weichselbaum R.R. Fu Y.X. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment.Blood. 2009; 114: 589-595Crossref PubMed Scopus (1070) Google Scholar, 4Takeshima T. Chamoto K. Wakita D. Ohkuri T. Togashi Y. Shirato H. Kitamura H. Nishimura T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy.Cancer Res. 2010; 70: 2697-2706Crossref PubMed Scopus (194) Google Scholar, 5Meng Y. Beckett M.A. Liang H. Mauceri H.J. van Rooijen N. Cohen K.S. Weichselbaum R.R. Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy.Cancer Res. 2010; 70: 1534-1543Crossref PubMed Scopus (147) Google Scholar Lee et al3Lee Y. Auh S.L. Wang Y. Burnette B. Meng Y. Beckett M. Sharma R. Chin R. Tu T. Weichselbaum R.R. Fu Y.X. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment.Blood. 2009; 114: 589-595Crossref PubMed Scopus (1070) Google Scholar demonstrated that CD8+ T cells partially mediated the therapeutic effects of radiation, whereas Apetoh et al2Apetoh L. Ghiringhelli F. Tesniere A. Obeid M. Ortiz C. Criollo A. Mignot G. Maiuri M.C. Ullrich E. Saulnier P. Yang H. Amigorena S. Ryffel B. Barrat F.J. Saftig P. Levi F. Lidereau R. Nogues C. Mira J.P. Chompret A. Joulin V. Clavel-Chapelon F. Bourhis J. Andre F. Delaloge S. Tursz T. Kroemer G. Zitvogel L. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.Nat Med. 2007; 13: 1050-1059Crossref PubMed Scopus (2473) Google Scholar identified Toll-like receptor 4–positive (TLR4+) dendritic cells as potent immunostimulatory cells capable of processing and presenting antigen from dying irradiated tumor cells. As a whole, there is increasing evidence of immune involvement in the anticancer effects of radiotherapy; however, the exact mechanisms governing this response are largely unknown and may differ from one malignancy to another. Irradiation of normal tissue, and now more recently described, tumor tissue, induces an inflammatory state often resulting in the secretion of cytokines into the microenvironment.6Kim K. McBride W.H. Modifying radiation damage.Curr Drug Targets. 2010; 11: 1352-1365Crossref PubMed Scopus (21) Google Scholar, 7Demaria S. Bhardwaj N. McBride W.H. Formenti S.C. Combining radiotherapy and immunotherapy: a revived partnership.Int J Radiat Oncol Biol Phys. 2005; 63: 655-666Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 8McBride W.H. Chiang C.S. Olson J.L. Wang C.C. Hong J.H. Pajonk F. Dougherty G.J. Iwamoto K.S. Pervan M. Liao Y.P. A sense of danger from radiation.Radiat Res. 2004; 162: 1-19Crossref PubMed Scopus (280) Google Scholar, 9Formenti S.C. Demaria S. Systemic effects of local radiotherapy.Lancet Oncol. 2009; 10: 718-726Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar This is likely the result of danger signals released by damaged or dying cells in response to DNA strand breaks.8McBride W.H. Chiang C.S. Olson J.L. Wang C.C. Hong J.H. Pajonk F. Dougherty G.J. Iwamoto K.S. Pervan M. Liao Y.P. A sense of danger from radiation.Radiat Res. 2004; 162: 1-19Crossref PubMed Scopus (280) Google Scholar Whereas once largely ignored, it is now appreciated that these cytokines may impact the effectiveness of radiotherapy, or by to or as as inducing or a immune of a cytokine with effects on tumors is interferon gamma IFN-γ, an inflammatory cytokine that determined was following radiation in a melanoma A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar has as to tumor G. of in Cancer Res. PubMed Scopus Google Scholar of this cytokine direct effects on tumor cells as as of the of the immune system tumor A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar However, reports have the efficacy of IFN-γ as an antitumor where IFN-γ to tumor G. of in Cancer Res. PubMed Scopus Google Scholar on the IFN-γ was to of B16 to the as as stimulate the of K. M. P. R. G. K. gamma induces by B16 melanoma cells in with of A. PubMed Scopus Google Scholar, D. interferon in Biol Full Text Full Text PDF PubMed Scopus Google Scholar IFN-γ the antitumor of cells and through the of T cells with the of T. of in malignant melanoma T cells to immune and 2009; PubMed Scopus Google Scholar, in and immune PubMed Scopus Google Scholar, as a of on PubMed Scopus Google Scholar, S. P. cells: and Immunol. 2009; PubMed Scopus Google Scholar in a as tumor radiotherapy in which the efficacy on a potent immune IFN-γ is or with to the immune system following radiotherapy. this determined that IFN-γ was not was essential in mediating the antitumor effects of radiation in a mouse colon induction in of of the colon in mice for chemotherapy with a on Res. Google Scholar IFN-γ was in the tumor 2 days following radiation, and CD8+ T cells were the producers of this Elimination of CD8+ T cells, not reduced the intratumoral levels of IFN-γ, abrogated antitumor effect of demonstrated that IFN-γ had no direct effect on tumor cells in tumor it the capacity of T cells, in an resulting in a decrease of tumor and mice were from the IFN-γ reporter for M. J.L. Wang L. M. cytokine and T cells for effector Med. PubMed Scopus Google Scholar were from of at mice were in to by the on induction in of of the colon in mice for chemotherapy with a on Res. Google Scholar a colon adenocarcinoma, was from and in with and receptor and were by with a an IFN-γ as previously A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar were with cells into the was using and was of the where is the and is the were and local directly to the days following tumor as previously A.A. Moran J.P. Gerber S.A. Rose R.C. Frelinger J.G. Lord E.M. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor.J Immunol. 2005; 174: 7516-7523Crossref PubMed Scopus (761) Google Scholar were for on CD8+ T cells, mice were with of in tumor and days in was used as a levels of IFN-γ, of tumor was and in of S.A. induces of to of Immunol. PubMed Scopus Google Scholar and on for to using a were at for and was and for using a or for IFN-γ by to the IFN-γ was to were as previously Frelinger J.G. Lord E.M. of T of a tumor.J Immunol. 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PubMed Scopus Google Scholar used for were as and of interferon factor and were into as were as with and CD8+ cells were using a cell and in was using an to the and using a for and was by as previously S.A. induces of to of Immunol. PubMed Scopus Google Scholar using to an were to and as over were by on as previously S.A. Moran J.P. Frelinger J.G. Frelinger Lord E.M. of mediated in using J PubMed Scopus Google Scholar, S.A. A.A. Frelinger J.G. Lord E.M. of tumor to immune and role of a in and J Full Text Full Text PDF PubMed Scopus Google Scholar were as and were using to were for the to lyse cells in a 51Cr release are as from at were for using or a of by a Our data have demonstrated the of an immune response in mediating the antitumor effects of radiotherapy in a melanoma A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar the role of IFN-γ in antitumor mice with cells into wild-type or IFNγKO mice. were or with days and was over A of radiation was used data that a greater antitumor immune response to a A.A. Moran J.P. Gerber S.A. Rose R.C. Frelinger J.G. Lord E.M. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor.J Immunol. 2005; 174: 7516-7523Crossref PubMed Scopus (761) Google Scholar tumors in mice were therapy not have an impact on growth in mice tumors for 2 days following therapy However, a decrease of tumor burden was tumors at a to control Interestingly, tumors in IFNγKO and mice radiation treatment was in tumor growth in IFNγKO mice IFN-γ was within the tumor tumor from and mice were for IFN-γ by results were to IFN-γ was following radiotherapy on days and to the of IFN-γ in irradiated over tumor over and that cytokine induction is on IR However, levels of IFN-γ are increased on and to This in the of IFN-γ with the decrease of tumor burden following radiotherapy at the data that levels of IFN-γ are increased following radiotherapy. More importantly, have identified IFN-γ as an essential cytokine that to the antitumor effects of radiation therapy. the by which IFN-γ mediates the antitumor effects of radiotherapy, IFN-γ was directly cytotoxic to tumor cells. cells were with an IFN-γ these cells to IFN-γ as demonstrated by to or following and treatments of IFN-γ in were to following IFN-γ in not in on tumor cells in and on of tumor growth that the tumors levels of and exhibited to tumors We the growth of and tumors with or radiation as tumor in More importantly, radiation was able to control tumor growth in a in and IFN-γ is not directly on tumor cells to the antitumor effects of radiotherapy. 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We immune cells within the tumor using used IFN-γ reporter mice in which of the results in reporter immune cells IFN-γ be tumors were in or mice and with or radiation as were and were for by A that was not in mice was in tumor that cells for IFN-γ on were CD8+ T cells and cells of cells were CD8+ T cells. were irradiated and tumor with to immune mice for IFN-γ not the K. P. M. of effector T cells in response to is to the for Immunol. 2005; 174: PubMed Scopus Google Scholar to IFN-γ used intracellular IFN-γ staining of immune from mice as in and cells were primarily in the cells further by cells were determined to be predominantly CD8+ T cells of CD8+ T cells increased in tumors from to More importantly, the of CD8+ T cells on and and days following radiation results from the mice and intracellular IFN-γ staining identified CD8+ T cells as the producers of IFN-γ. the of the that of CD8+ T cells result in levels of IFN-γ. CD8+ T cells with of of tumor and days was used as a treatment in a of CD8+ T cells in the tumor and not were with tumor and irradiated as CD8+ in a decrease in levels of IFN-γ at and that CD8+ T cells are the predominant producers of IFN-γ We tumor growth with and radiation and mice. growth was in tumors the However, the antitumor effects of radiation were completely in mice that were of CD8+ T cells, and had levels of IFN-γ data CD8+ T cells as an essential cell required to the antitumor effects of radiotherapy. A new and concept has that the immune system plays a pivotal role in mediating the antitumor effects of radiation therapy. reports have the contribution of dendritic cells in the of tumor antigen to the of CD8+ T cells in an antitumor response following L. Ghiringhelli F. Tesniere A. Obeid M. Ortiz C. Criollo A. Mignot G. Maiuri M.C. Ullrich E. Saulnier P. Yang H. Amigorena S. Ryffel B. Barrat F.J. Saftig P. Levi F. Lidereau R. Nogues C. Mira J.P. Chompret A. Joulin V. Clavel-Chapelon F. Bourhis J. Andre F. Delaloge S. Tursz T. Kroemer G. Zitvogel L. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.Nat Med. 2007; 13: 1050-1059Crossref PubMed Scopus (2473) Google Scholar, 3Lee Y. Auh S.L. Wang Y. Burnette B. Meng Y. Beckett M. Sharma R. Chin R. Tu T. Weichselbaum R.R. Fu Y.X. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment.Blood. 2009; 114: 589-595Crossref PubMed Scopus (1070) Google Scholar, 4Takeshima T. Chamoto K. Wakita D. Ohkuri T. Togashi Y. Shirato H. Kitamura H. Nishimura T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy.Cancer Res. 2010; 70: 2697-2706Crossref PubMed Scopus (194) Google Scholar, A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar Our a contribution to the of the immune response following radiotherapy mediates tumor demonstrated that the Th1 IFN-γ, which was predominantly by CD8+ T cells, was essential to the antitumor effects of This is reports suggest that IFN-γ may be to tumor G. of in Cancer Res. PubMed Scopus Google Scholar Our studies from these reports in that the role of IFN-γ in tumor control in response to radiation therapy within a tumor data in the of radiotherapy, the of IFN-γ in tumors is and effective antitumor cytotoxic T cells that are We IFN-γ by immune cells using mice and intracellular staining for of mice is that they for IFN-γ through however, this not that IFN-γ is et K. P. M. of effector T cells in response to is to the for Immunol. 2005; 174: PubMed Scopus Google Scholar determined that T cells cells IFN-γ required an as or to IFN-γ through for cells that have the to IFN-γ. This concept can be to and is in where the of CD8+ T cells are and have the to IFN-γ Interestingly, intracellular staining that of CD8+ T cells for IFN-γ not We were to that not in response to radiation an of IFN-γ CD8+ T cells from irradiated data suggest that radiation, or the effects of radiation may an that cells with the to IFN-γ to and release this is that radiotherapy results in damage and the of danger signals to molecular or molecular W.H. Chiang C.S. Olson J.L. Wang C.C. Hong J.H. Pajonk F. Dougherty G.J. Iwamoto K.S. Pervan M. Liao Y.P. A sense of danger from radiation.Radiat Res. 2004; 162: 1-19Crossref PubMed Scopus (280) Google Scholar danger signals have the to a tumor through the of cytokines as tumor necrosis factor and W.H. Chiang C.S. Olson J.L. Wang C.C. Hong J.H. Pajonk F. Dougherty G.J. Iwamoto K.S. Pervan M. Liao Y.P. A sense of danger from radiation.Radiat Res. 2004; 162: 1-19Crossref PubMed Scopus (280) Google Scholar danger signals have to directly immune cells. signals as and can stimulate the of dendritic W.H. Chiang C.S. Olson J.L. Wang C.C. Hong J.H. Pajonk F. Dougherty G.J. Iwamoto K.S. Pervan M. Liao Y.P. A sense of danger from radiation.Radiat Res. 2004; 162: 1-19Crossref PubMed Scopus (280) Google Scholar, S. P. to the immune Immunol. 13: PubMed Scopus Google Scholar, Y. of a danger that the immune system to dying PubMed Scopus Google Scholar it is that danger signals may be on CD8+ T cells to stimulate the of IFN-γ and secretion into the tumor Our data CD8+ T cells as essential in mediating the antitumor effects of cells are not for the of IFN-γ following radiation, are likely the effector cell capable of tumor cells Interestingly, the of CD8+ T cells were not increased in irradiated tumors on effector and CD8+ T cells from irradiated tumors were to CD8+ T cells from tumors as by not CD8+ T cells from or irradiated Our data suggest that T cells from irradiated tumors tumor or This that the cells are within the irradiated tumor this to T cells from irradiated tumors is dependent on IFN-γ. We that CD8+ T cells are by danger signals within the tumor which the of IFN-γ by these cells. 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IFN-γ has to or cytotoxic effects directly on tumor cells. the capacity of is in a these cells are with IFN-γ in not However, data IFN-γ directly on in an tumor growth was not in or irradiated tumors to however, not from the of the direct effects of IFN-γ in We have previously that IFN-γ was required to on tumor cells following radiation in a B16 tumor A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. PubMed Scopus Google Scholar This of likely plays an role in tumor antigen to effector CD8+ T cells, thereby facilitating immune This is in to model in which demonstrated that IFN-γ not act directly on tumor cells to tumor its effects may be cytotoxic cells. 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J. the role of the tumor in 2007; PubMed Scopus Google Scholar, or effects of the in 2004; PubMed Scopus Google Scholar cell may a resulting in tumor D. to the of cells to the tumor Full Text Full Text PDF PubMed Scopus Google Scholar However, can be that could an to an IFN-γ is an essential factor that the response tumor thereby reducing tumor This factor was within the tumor and not by and within the of these mice not data the of IFN-γ within the tumor as this cytokine was to stimulate T cells to tumor cells, was not required to act directly on tumor cells to tumor cell that IFN-γ are within the tumor and could be for this G. L. F. M. G. G. G. of receptor in J Immunol. PubMed Scopus Google Scholar IFN-γ can act directly on cells to cell K.S. induces through DNA damage signaling in 2009; PubMed Scopus Google Scholar work has demonstrated that IFN-γ the cell on tumor A.A. Gerber S.A. Moran J.P. Frelinger J.G. Lord E.M. within the tumor antitumor Immunol. 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PubMed Scopus Google Scholar an treatment the of this cytokine directly to the tumor as or may be a of IFN-γ to the E. tumor with induction of tumor and potent antitumor Res. Google Scholar, J. D. A. Lord E. M. Frelinger J. of an that can be by PubMed Scopus Google Scholar We that the efficacy of radiotherapy can be by increasing the levels of IFN-γ at the or radiation studies are the therapeutic of radiotherapy with IFN-γ in the tumor as as tumors to that the effectiveness of the treatment is Additional be this has the to radiation in the We E. J. and for in of the and for tumor cells. with cells of IFN-γ receptor and reduced were with or cells. were and into a days IFN-γ receptor levels and on tumor cells was by and as