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• W3020551799 abstract "The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase 3 clinical trial design has lagged in settings of advanced locoregional disease, where combination with radiation therapy may be critical. Yet, such may be the settings where immunotherapies have their greatest potential to affect patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment antitumor immunity through combined-modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation, and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical effect may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach are highly warranted. The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase 3 clinical trial design has lagged in settings of advanced locoregional disease, where combination with radiation therapy may be critical. Yet, such may be the settings where immunotherapies have their greatest potential to affect patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment antitumor immunity through combined-modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation, and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical effect may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach are highly warranted. Radiation therapy is a mainstay of cancer therapy, with more than 60% of patients receiving radiation in the form of definitive, adjuvant, or palliative treatment. Growing evidence dating to the 1970s demonstrates that the immune system contributes to the antitumor effect generated by radiation.1Stone H.B. Peters L.J. Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma.J Natl Cancer Inst. 1979; 63: 1229-1235PubMed Google Scholar Although classically thought of as a locoregional therapy, radiation has the potential to generate out of field “abscopal” antitumor responses,2Demaria S. Ng B. Devitt M.L. et al.Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated.Int J Radiat Oncol Biol Phys. 2004; 58: 862-870Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar with current evidence suggesting that immunologic mechanisms underscore this effect.3Formenti S.C. Demaria S. Systemic effects of local radiotherapy.Lancet Oncol. 2009; 10: 718-726Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar Although the abscopal effect is exceedingly rare with radiation therapy alone,4Abuodeh Y. Venkat P. Kim S. Systematic review of case reports on the abscopal effect.Curr Probl Cancer. 2016; 40: 25-37Crossref PubMed Scopus (212) Google Scholar these observations of immune-mediated effects of radiation have led to growing enthusiasm for the potential of immunotherapies to augment the locoregional efficacy of radiation therapy and conversely for radiation therapy to help prime a more effective systemic antitumor response to immunotherapies. Immunotherapies are cancer treatments that seek to engage the patient’s own immune system to eradicate tumor cells. The historical development of immunotherapy shares many parallels with that of radiation therapy. As with radiation, initial clinical application of an immunotherapy was reported in the late 19th century. William Coley pioneered the use of a bacterial preparation termed Coley’s toxin in the 1890s. Although the clinical effect was modest, Coley’s toxin provided an early demonstration of the potential to generate an antitumor response by harnessing the immune system. Mirroring radiation, immunotherapies gained prominence as a component of standard cancer treatment in the mid- to late-20th century, albeit with considerable toxicities. This included the origins of cell therapies with the development of bone marrow transplant by Fritz Bach and others in the 1960s5Bach F.H. Albertini R.J. Joo P. Anderson J.L. Bortin M.M. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome.Lancet. 1968; 2: 1364-1366Abstract PubMed Google Scholar and the production, testing, and clinical approval of high dose interleukin 2 (IL-2) for metastatic renal cell carcinoma6Fyfe G.A. Fisher R.I. Rosenberg S.A. Sznol M. Parkinson D.R. Louie A.C. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy.J Clin Oncol. 1996; 14: 2410-2411Crossref PubMed Scopus (138) Google Scholar and melanoma in the 1990s.7Atkins M.B. Lotze M.T. Dutcher J.P. et al.High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993.J Clin Oncol. 1999; 17: 2105-2116Crossref PubMed Google Scholar In the 21st century, more selective targeting significantly reduced the toxicities of both radiation and immunotherapies. In radiation oncology, this resulted largely from technological advances, including highly conformal intensity modulated and stereotactic techniques combined with high-precision image guidance.8Hong T.S. Ritter M.A. Tome W.A. Harari P.M. Intensity-modulated radiation therapy: Emerging cancer treatment technology.Br J Cancer. 2005; 92: 1819-1824Crossref PubMed Scopus (59) Google Scholar,9Blomgren H. Lax I. Naslund I. Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients.Acta Oncol. 1995; 34: 861-870Crossref PubMed Scopus (657) Google Scholar Prominent advances with immunotherapies include the development of antibodies directly targeting tumor cells, immune checkpoint inhibitor antibodies, and chimeric antigen receptor T cell therapies.10Gross G. Waks T. Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.Proc Natl Acad Sci USA. 1989; 86: 10024-10028Crossref PubMed Scopus (815) Google Scholar Immune checkpoint inhibitor antibodies have revolutionized the approach to treating metastatic disease in several cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma, with some patients experiencing complete responses durable to over 5 years.11Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar,12Topalian S.L. Hodi F.S. Brahmer J.R. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.JAMA Oncol. 2019; 5: 1411-1420Crossref PubMed Scopus (167) Google Scholar Currently there are approved therapies targeting 2 immune checkpoints: CTLA-4 and PD-1/PD-L1. The increasing specificity of modern radiation therapy and immunotherapies has reduced toxicity profiles and facilitated their increasing roles in clinical oncology. This historical convergence in increased clinical safety and advancement of radiation and immunotherapy now makes feasible their inclusion as part of combined-modality treatment approaches (Fig. 1). The Steel hypothesis, first conceptualized in the 1970s, describes mechanisms whereby combined-modality drug/radiation approaches could improve treatment outcomes.13Steel G.G. Terminology in the description of drug-radiation interactions.Int J Radiat Oncol Biol Phys. 1979; 5: 1145-1150Abstract Full Text PDF PubMed Scopus (151) Google Scholar A modernization of the Steel hypothesis has been described, highlighting exploitable interactions of radiation and cancer drugs in the molecular era.14Bentzen S.M. Harari P.M. Bernier J. Exploitable mechanisms for combining drugs with radiation: Concepts, achievements and future directions.Nat Clin Pract Oncol. 2007; 4: 172-180Crossref PubMed Scopus (101) Google Scholar Under this revised framework, radiation and immunotherapy agents may interact to improve clinical outcomes through 5 distinct mechanisms: (1) spatial cooperation, (2) temporal modulation, (3) biological cooperation, (4) cytotoxic enhancement, and (5) normal tissue protection. Through mechanisms described in the following, radiation has the potential to increase susceptibility of tumor cells to immune-mediated killing.15Demaria 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 (255) Google Scholar These radiated tumor cells also upregulate negative feedback elements (eg, checkpoint proteins), which can dampen the immune response.16Twyman-Saint Victor C. Rech A.J. Maity A. et al.Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.Nature. 2015; 520: 373-377Crossref PubMed Scopus (1335) Google Scholar,17Vanpouille-Box C. Alard A. Aryankalayil M.J. et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.Nat Commun. 2017; 8: 15618Crossref PubMed Scopus (638) Google Scholar Immunotherapy agents blocking this negative feedback may reinvigorate an immune response that was primed by radiation (Fig. 2). This biological cooperation resulting from intersecting cellular and signaling mechanisms has potential to enable spatial cooperation through generation of systemic immune responses mounted against distant, out-of-field tumors and cytotoxic enhancement via increased immune killing of radiated tumor cells.2Demaria S. Ng B. Devitt M.L. et al.Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated.Int J Radiat Oncol Biol Phys. 2004; 58: 862-870Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar,18Demaria S. Kawashima N. Yang A.M. 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. 2005; 11: 728-734PubMed Google Scholar Responses to immunotherapy often are delayed compared with other forms of cancer treatment and may follow a transient increase in tumor burden. This has prompted development of new criteria for evaluation of response to immunotherapies.19Hodi F.S. Ballinger M. Lyons B. et al.Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining guidelines to assess the clinical benefit of cancer immunotherapy.J Clin Oncol. 2018; 36: 850-858Crossref PubMed Scopus (139) Google Scholar This raises concerns that, in rapidly proliferating tumors, patients who would otherwise have mounted an effective immune response may succumb to sequela of transient progression (eg, airway obstruction). Radiation can reduce the growth of such lesions, allowing a greater window of opportunity for response to immunotherapy, thereby eliciting temporal modulation. Immunotherapy also has the potential to promote normal tissue protection, and current investigational strategies include antibody-mediated blocking of radiation-induced fibrosis by targeting TGFβ. As these examples illustrate, the Steel hypothesis provides a framework for conceptualizing the potential cooperative therapeutic interactions between radiation therapy and immunotherapies. In this article, we review these interactions through a discussion of illustrative preclinical and clinical studies that investigate combinations of radiation and immunotherapy. A growing body of eloquent preclinical work describes the immunogenic effects of radiation on the tumor microenvironment. Radiation can induce immunogenic tumor cell death and release of tumor-specific antigens.20Kroemer G. Galluzzi L. Kepp O. Zitvogel L. Immunogenic cell death in cancer therapy.Annu Rev Immunol. 2013; 31: 51-72Crossref PubMed Scopus (1495) Google Scholar,21Golden E.B. Frances D. Pellicciotta I. Demaria S. Helen Barcellos-Hoff M. Formenti S.C. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death.Oncoimmunology. 2014; 3e28518Crossref PubMed Scopus (260) Google Scholar Tumor cells surviving radiation may not escape unscathed and undergo phenotypic changes in the expression of immune susceptibility markers.15Demaria 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 (255) Google Scholar Effects on the microenvironment include temporary local eradication of radiation-sensitive immune lineages, including suppressor and effector lymphocytes, and local release of inflammatory cytokines and damage-associated molecular patterns resulting in local effects on endothelial cell expression of adhesion receptors, immune cell trafficking, and immune cell activation.22Rodriguez-Ruiz M.E. Garasa S. Rodriguez I. et al.Intercellular adhesion molecule-1 and vascular cell adhesion molecule are induced by ionizing radiation on lymphatic endothelium.Int J Radiat Oncol Biol Phys. 2017; 97: 389-400Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,23Waldmann T.A. Cytokines in cancer immunotherapy.Cold Spring Harb Perspect Biol. 2018; 10: a028472Crossref PubMed Scopus (113) Google Scholar On the other hand, radiation also triggers effects in the tumor microenvironment that are potentially detrimental to the development of antitumor immunity. These include delayed increases in tumor infiltration by suppressive regulatory T cells and increased infiltration and activation of inhibitory macrophage and myeloid-derived suppressor cell lineages.24Fridlender Z.G. Sun J. Kim S. et al.Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN.Cancer Cell. 2009; 16: 183-194Abstract Full Text Full Text PDF PubMed Scopus (1611) Google Scholar, 25Kachikwu E.L. Iwamoto K.S. Liao Y.P. et al.Radiation enhances regulatory T cell representation.Int J Radiat Oncol Biol Phys. 2011; 81: 1128-1135Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 26Tanaka H. Shinto O. Yashiro M. et al.Transforming growth factor beta signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity.Oncol Rep. 2010; 24: 1637-1643Crossref PubMed Scopus (52) Google Scholar, 27Tsai C.S. Fang-Hsin C. Wang C.C. et al.Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth.Int J Radiat Oncol Biol Phys. 2007; 68: 499-507Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 28Xu J. Escamilla J. Mok S. et al.CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer.Cancer Res. 2013; 73: 2782-2794Crossref PubMed Scopus (320) Google Scholar In addition, certain pathways influenced by radiation can have both positive and negative effects on antitumor immunity and the tumor microenvironment. For example, production of type 1 interferon can induce recruitment of effector T cells and antigen presenting cells, but it can also drive recruitment of myeloid-derived suppressor cells.29Liang H. Deng L. Hou Y. et al.Host STING-dependent MDSC mobilization drives extrinsic radiation resistance.Nat Commun. 2017; 8: 1736Crossref PubMed Scopus (142) Google Scholar Additionally, prolonged activation of type 1 and 2 interferon can drive expression of ligands for multiple T cell inhibitory receptors.30Benci J.L. Xu B. Qiu Y. et al.Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade.Cell. 2016; 167: 1540-1554.e12Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar Targeting such detrimental immunologic effects is an approach whereby immunotherapies may be used to augment the efficacy of radiation therapy. Dose, fractionation, and volume of radiation influence immunologic effects in the tumor microenvironment. Fractionation of radiation generally enables relative sparing of normal tissues while achieving therapeutic dose delivery to cancer cells. Differences in the capacity and kinetics of DNA damage repair in normal tissues versus tumor cells underlie the rationale for this approach. However, fractionation does not spare adaptive immune cell populations, specifically lymphocytes, which have little capacity for DNA damage repair and undergo apoptosis within hours of exposure to single-fraction doses of just 1 to 3 Gy.31Kaur P. Asea A. Radiation-induced effects and the immune system in cancer.Front Oncol. 2012; 2: 191Crossref PubMed Google Scholar Radiation-induced lymphopenia is a negative prognostic factor, and multiple studies indicate that it is positively correlated with field size, dose per fraction, and fraction number.32Rosen E.M. Fan S. Rockwell S. Goldberg I.D. The molecular and cellular basis of radiosensitivity: Implications for understanding how normal tissues and tumors respond to therapeutic radiation.Cancer Invest. 1999; 17: 56-72Crossref PubMed Google Scholar,33Ellsworth S.G. Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors.Adv Radiat Oncol. 2018; 3: 512-519Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Additional clinical data suggest that absolute lymphocyte count is predictive of response to checkpoint blockade and is positively correlated with response rate and duration of response.34Diehl A. Yarchoan M. Hopkins A. Jaffee E. Grossman S.A. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors.Oncotarget. 2017; 8: 114268-114280Crossref PubMed Scopus (92) Google Scholar On the other hand, preclinical studies suggest that despite an initial local depletion of lymphocytes, hypofractionated regimens of radiation may be immune activating.35Dewan M.Z. Galloway A.E. Kawashima N. et al.Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.Clin Cancer Res. 2009; 15: 5379-5388Crossref PubMed Scopus (919) Google Scholar Recent work suggests that standard fractionation and hypofractionation induce expansion of unique immune populations, with standard fractionation favoring a myeloid response and hypofractionation driving a lymphoid response that may be more favorable to adaptive antitumor immunity.36Grapin M. Richard C. Limagne E. et al.Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: A promising new combination.J Immunother Cancer. 2019; 7: 160Crossref PubMed Scopus (48) Google Scholar Such analyses of fractionation are challenging to control, however, in light of the confounding effects of time and the dynamic nature of changes in tumor-infiltrating immune cells. Immunogenic tumor cell death increases as a function of increasing dose.37Fowler J.F. The linear-quadratic formula and progress in fractionated radiotherapy.Br J Radiol. 1989; 62: 679-694Crossref PubMed Scopus (1631) Google Scholar High-dose radiation also leads to dose-dependent increases in the expression of MHC-1 and death receptors such as Fas, which are critical for T cell killing of tumor cells.38Werner L.R. Kler J.S. Gressett M.M. et al.Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma.Radiother Oncol. 2017; 124: 418-426Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,39Reits E.A. Hodge J.W. Herberts C.A. et al.Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy.J Exp Med. 2006; 203: 1259-1271Crossref PubMed Scopus (947) Google Scholar In contrast, moderate fractional doses of 8 to 12 Gy may be optimal for activating a type I interferon response in tumor cells via a dose-dependent increase in the cytoplasmic leakage of DNA from micronuclei, which activates the cGAS/STING pathway.17Vanpouille-Box C. Alard A. Aryankalayil M.J. et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.Nat Commun. 2017; 8: 15618Crossref PubMed Scopus (638) Google Scholar,40Harding S.M. Benci J.L. Irianto J. Discher D.E. Minn A.J. Greenberg R.A. Mitotic progression following DNA damage enables pattern recognition within micronuclei.Nature. 2017; 548: 466-470Crossref PubMed Scopus (507) Google Scholar At higher doses, radiation-induced STING activation may decline in part because of induced expression of Trex1 exonuclease, which reduces the accumulation of cytoplasmic DNA, resulting in negative feedback inhibition.17Vanpouille-Box C. Alard A. Aryankalayil M.J. et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.Nat Commun. 2017; 8: 15618Crossref PubMed Scopus (638) Google Scholar In preclinical studies, activation of the cGAS/STING pathway has been essential for generating radiation-induced adaptive immune responses,17Vanpouille-Box C. Alard A. Aryankalayil M.J. et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.Nat Commun. 2017; 8: 15618Crossref PubMed Scopus (638) Google Scholar,41Deng L. Liang H. Xu M. et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors.Immunity. 2014; 41: 843-852Abstract Full Text Full Text PDF PubMed Scopus (821) Google Scholar and the complexity of this interaction extends beyond tumor intrinsic signaling. For example, immune recognition of radiated tumors requires dendritic cell–intrinsic STING activation via cytoplasmic sensing of tumor-derived DNA,41Deng L. Liang H. Xu M. et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors.Immunity. 2014; 41: 843-852Abstract Full Text Full Text PDF PubMed Scopus (821) Google Scholar which may be mediated in part by uptake of tumor-derived exosomes containing tumor cell DNA fragments.42Diamond J.M. Vanpouille-Box C. Spada S. et al.Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs.Cancer Immunol Res. 2018; 6: 910-920Crossref PubMed Scopus (118) Google Scholar At low doses (2-5 Gy), radiation modulates the tumor microenvironment by inducing the release of cytokines that influence immune cell trafficking and activation.22Rodriguez-Ruiz M.E. Garasa S. Rodriguez I. et al.Intercellular adhesion molecule-1 and vascular cell adhesion molecule are induced by ionizing radiation on lymphatic endothelium.Int J Radiat Oncol Biol Phys. 2017; 97: 389-400Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,43Liu S.Z. Nonlinear dose-response relationship in the immune system following exposure to ionizing radiation: Mechanisms and implications.Nonlinearity Biol Toxicol Med. 2003; 1: 71-92Crossref PubMed Google Scholar At low doses (1-3 Gy), radiation also may modulate the tumor microenvironment by ablating radiation-sensitive immune populations, including suppressive and effector lymphocytes.44Nakamura K.Y.N. Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay.Radiat Res. 1990; 123: 224-227Crossref PubMed Scopus (115) Google Scholar, 45Liu R. Xiong S. Zhang L. Chu Y. Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatory cells.Cell Mol Immunol. 2010; 7: 157-162Crossref PubMed Scopus (47) Google Scholar, 46Liu S. Sun X. Luo J. et al.Effects of radiation on T regulatory cells in normal states and cancer: mechanisms and clinical implications.Am J Cancer Res. 2015; 5: 3276-3285PubMed Google Scholar, 47Balogh A. Persa E. Bogdandi E.N. et al.The effect of ionizing radiation on the homeostasis and functional integrity of murine splenic regulatory T cells.Inflamm Res. 2013; 62: 201-212Crossref PubMed Scopus (50) Google Scholar This may create a window of opportunity by locally and temporarily depleting exhausted and suppressive T cells from the tumor microenvironment and allowing reconstitution with a more favorable infiltrate using immunotherapies. In preclinical and clinical studies, several groups have taken advantage of the favorable immunomodulatory effects of radiation to prime a more effective systemic antitumor immune response.48Morris Z.S. Guy E.I. Francis D.M. et al.In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments.Cancer Res. 2016; 76: 3929-3941Crossref PubMed Scopus (55) Google Scholar, 49Marabelle A. Tselikas L. de Baere T. Houot R. Intratumoral immunotherapy: Using the tumor as the remedy.Ann Oncol. 2017; 28: xii33-xii43Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 50Pierce R.H. Campbell J.S. Pai S.I. Brody J.D. Kohrt H.E. In-situ tumor vaccination: Bringing the fight to the tumor.Hum Vaccin Immunother. 2015; 11: 1901-1909Crossref PubMed Scopus (39) Google Scholar This treatment strategy, termed in situ vaccination, uses a patient’s own tumor as a source of tumor-specific antigen to stimulate and diversify an effective antitumor T cell response. This approach takes advantage of “private antigens,” which are induced by random, patient-specific mutations and differentiation markers in tumor cells. Recent evidence suggests that these mutated proteins are the most important tumor antigens recognized by T cells.51Campbell B.B. Light N. Fabrizio D. et al.Comprehensive analysis of hypermutation in human cancer.Cell. 2017; 171: 1042-1056.e10Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Through the capacity to immunomodulate the tumor microenvironment and generate an in situ vaccination effect, radiation may play a role in rendering tumors more responsive to immunotherapies. Preclinical evidence provides a clear rationale for the combination of radiation with immune checkpoint blockade. Radiation can promote adaptive resistance through upregulation of PD-L1 on tumor cells,52Deng L. Lian H. Burnette B. et al.Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice.J Clin Invest. 2014; 124: 687-695Crossref PubMed Scopus (1069) Google Scholar and the addition of checkpoint blockade can overcome this resistance mechanism and enhance the generation of abscopal responses.53Dovedi S.J. Cheadle E.J. Popple Al et al.Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade.Clin Cancer Res. 2017; 23: 5514-5526Crossref PubMed Scopus (154) Google Scholar Combination with radiation may be particularly valuable in the treatment of immunologically “cold” tumors, which are characterized by low levels of T cell infiltrate and low mutation burden, resulting in few mutation-created neo-antigens.54Gajewski T.F. The next hurdle in cancer immunotherapy: Overcoming the non-T-cell-inflamed tumor microenvironment.Semin Oncol. 2015; 42: 663-671Crossref PubMed Scopus (235) Google Scholar Such “cold” tumors do not typically respond to immunotherapies such as immune checkpoint inhibitors.16Twyman-Saint Victor C. Rech A.J. Maity A. et al.Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.Nature. 2015; 520: 373-377Crossref PubMed Scopus (1335) Google Scholar,18Demaria S. Kawashima N. Yang A.M. 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. 2005; 11: 728-734PubMed Google Scholar Even in tumors that are responsive to immune checkpoint blockade or other immunotherapies, radiation may allow for increased depth and duration of response by priming a more diversified adaptive antitumor immune response. For example, in the B16 murine model of melanoma, radiation and checkpoint blockade activated separate immunologic mechanisms: diversification of the repertoire of T cell receptors among tumor-infiltrating lymphocytes and increased" @default.
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• W3020551799 date "2020-09-01" @default.
• W3020551799 modified "2023-10-11" @default.
• W3020551799 title "The Promise of Combining Radiation Therapy With Immunotherapy" @default.
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