{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:01:27Z","timestamp":1790665287167,"version":"4.1.0"},"reference-count":103,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy. Similar to ICB, the efficacy of CAR-T therapy is also significantly impacted by the immunosuppressive TME, leading to compromised T cell function and\/or insufficient T cell infiltration. In this review, we will discuss some of the key barriers to the activity of CAR-T cells in the immunosuppressive TME and focus on how RT can be used to eliminate or bypass these barriers. We will present the challenges to achieving success with this therapeutic partnership. Looking forward, we will also provide strategies currently being investigated to ensure the success of this combination strategy in the clinic.<\/jats:p>","DOI":"10.3389\/fimmu.2021.813832","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T01:56:49Z","timestamp":1641952609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":50,"title":["CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors"],"prefix":"10.3389","volume":"12","author":[{"given":"Vicky Mengfei","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Haynes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Criselle","family":"D\u2019Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Neeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe Jiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cgt.7700710","article-title":"A Functional Role for CD28 Costimulation in Tumor Recognition by Single-Chain Receptor-Modified T Cells","volume":"11","author":"Moeller","year":"2004","journal-title":"Cancer Gene Ther"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709919","article-title":"Long-Term Follow-Up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia","volume":"378","author":"Park","year":"2018","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01109","article-title":"CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape","volume":"11","author":"Rodriguez-Garcia","year":"2020","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","article-title":"Approaches to Treat Immune Hot, Altered and Cold Tumours With Combination Immunotherapies","volume":"18","author":"Galon","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI91190","article-title":"IFN-Gamma-Related mRNA Profile Predicts Clinical Response to PD-1 Blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.2736","article-title":"Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma","volume":"33","author":"Schadendorf","year":"2015","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature13954","article-title":"PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-SITC2020.0241","article-title":"241 Clinical Outcomes of Metastatic Melanoma Patients With Liver Metastases Treated With Anti-PD-1 Monotherapy Versus Combination Ipilimumab\/Nivolumab","volume":"8","author":"Ma","year":"2020","journal-title":"J Immuno Therapy Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1200\/JCO.20.00605","article-title":"Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study","volume":"39","author":"Pelster","year":"2021","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00128","article-title":"Immune Infiltration and Prostate Cancer","volume":"5","author":"Strasner","year":"2015","journal-title":"Front Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3390\/cancers10010006","article-title":"Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy","volume":"10","author":"Martinez-Bosch","year":"2018","journal-title":"Cancers (Basel)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2014.03.024","article-title":"Estimating the Demand for Radiotherapy From the Evidence: A Review of Changes From 2003 to 2012","volume":"112","author":"Barton","year":"2014","journal-title":"Radiother Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7150\/thno.26225","article-title":"Hypoxia-Responsive Lipid-Poly-(Hypoxic Radiosensitized Polyprodrug) Nanoparticles for Glioma Chemo- and Radiotherapy","volume":"8","author":"Hua","year":"2018","journal-title":"Theranostics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s40425-019-0634-9","article-title":"Optimized Fractionated Radiotherapy With Anti-PD-L1 and Anti-TIGIT: A Promising New Combination","volume":"7","author":"Grapin","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1395996","article-title":"PD-1 Blockade Reverses Adaptive Immune Resistance Induced by High-Dose Hypofractionated But Not Low-Dose Daily Fractionated Radiation","volume":"7","author":"Morisada","year":"2018","journal-title":"Oncoimmunology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0246-1","article-title":"Inflammatory Microenvironment Remodelling by Tumour Cells After Radiotherapy","volume":"20","author":"McLaughlin","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1506-7","article-title":"Type I Interferons Induced by Radiation Therapy Mediate Recruitment and Effector Function of CD8(+) T Cells","volume":"63","author":"Lim","year":"2014","journal-title":"Cancer Immunol Immunother"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15618","article-title":"DNA Exonuclease Trex1 Regulates Radiotherapy-Induced Tumour Immunogenicity","volume":"8","author":"Vanpouille-Box","year":"2017","journal-title":"Nat Commun"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084076","article-title":"Improved Functionality of the Vasculature During Conventionally Fractionated Radiation Therapy of Prostate Cancer","volume":"8","author":"Potiron","year":"2013","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/srep46714","article-title":"Ionizing Radiation Abrogates the Pro-Tumorigenic Capacity of Cancer-Associated Fibroblasts Co-Implanted in Xenografts","volume":"7","author":"Grinde","year":"2017","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010333118","article-title":"ICAM-1 Orchestrates the Abscopal Effect of Tumor Radiotherapy","volume":"118","author":"Zhao","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.5.3132","article-title":"Radiation-Induced IFN-Gamma Production Within the Tumor Microenvironment Influences Antitumor Immunity","volume":"180","author":"Lugade","year":"2008","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1131-x","article-title":"Liver Metastasis Restrains Immunotherapy Efficacy via Macrophage-Mediated T Cell Elimination","volume":"27","author":"Yu","year":"2021","journal-title":"Nat Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000537","article-title":"Low-Dose Radiation Treatment Enhances Systemic Antitumor Immune Responses by Overcoming the Inhibitory Stroma","volume":"8","author":"Barsoumian","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.ijrobp.2018.01.071","article-title":"Targeting Myeloid-Derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy","volume":"101","author":"Lan","year":"2018","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000792","article-title":"High Dose-Rate Brachytherapy of Localized Prostate Cancer Converts Tumors From Cold to Hot","volume":"8","author":"Keam","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1757360","article-title":"Intravital Imaging Reveals Synergistic Effect of CAR T-Cells and Radiation Therapy in a Preclinical Immunocompetent Glioblastoma Model","volume":"9","author":"Murty","year":"2020","journal-title":"Oncoimmunology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.09.008","article-title":"Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape","volume":"26","author":"DeSelm","year":"2018","journal-title":"Mol Ther"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-1788","article-title":"NKG2D-Based CAR T Cells and Radiotherapy Exert Synergistic Efficacy in Glioblastoma","volume":"78","author":"Weiss","year":"2018","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000284","article-title":"Radiation Priming Chimeric Antigen Receptor T-Cell Therapy in Relapsed\/Refractory Diffuse Large B-Cell Lymphoma With High Tumor Burden","volume":"43","author":"Qu","year":"2020","journal-title":"J Immunother"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0551","article-title":"BCMA-Targeted CAR T-Cell Therapy Plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy","volume":"7","author":"Smith","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3958","article-title":"The Tumour Microenvironment After Radiotherapy: Mechanisms of Resistance and Recurrence","volume":"15","author":"Barker","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0007-1","article-title":"Targeting the Tumour Stroma to Improve Cancer Therapy","volume":"15","author":"Valkenburg","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2019.00160","article-title":"Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy","volume":"6","author":"Henke","year":"2019","journal-title":"Front Mol Biosci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01835","article-title":"The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96268","article-title":"Targeted Hypoxia Reduction Restores T Cell Infiltration and Sensitizes Prostate Cancer to Immunotherapy","volume":"128","author":"Jayaprakash","year":"2018","journal-title":"J Clin Invest"},{"key":"B37","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s41419-017-0061-0","article-title":"Defining the Role of the Tumor Vasculature in Antitumor Immunity and Immunotherapy","volume":"9","author":"Schaaf","year":"2018","journal-title":"Cell Death Dis"},{"key":"B38","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.ccell.2017.04.003","article-title":"Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy","volume":"31","author":"Spranger","year":"2017","journal-title":"Cancer Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1158\/1078-0432.CCR-19-1868","article-title":"Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade","volume":"26","author":"House","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.ccell.2019.05.004","article-title":"Cooperation Between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors","volume":"35","author":"Dangaj","year":"2019","journal-title":"Cancer Cell"},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1038\/s41417-021-00303-x","article-title":"Key Chemokines Direct Migration of Immune Cells in Solid Tumors","volume-title":"Cancer Gene Ther","author":"Kohli","year":"2021"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2017.25","article-title":"T-Lymphocyte Homing: An Underappreciated Yet Critical Hurdle for Successful Cancer Immunotherapy","volume":"97","author":"Sackstein","year":"2017","journal-title":"Lab Invest"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0271-z","article-title":"Immune Crosstalk in Cancer Progression and Metastatic Spread: A Complex Conversation","volume":"20","author":"Garner","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2627","article-title":"Multifactorial T-Cell Hypofunction That Is Reversible can Limit the Efficacy of Chimeric Antigen Receptor-Transduced Human T Cells in Solid Tumors","volume":"20","author":"Moon","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02453","article-title":"T Regulatory Cells and Priming the Suppressive Tumor Microenvironment","volume":"10","author":"Paluskievicz","year":"2019","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa0984","article-title":"A Single Dose of Peripherally Infused EGFRvIII-Directed CAR T Cells Mediates Antigen Loss and Induces Adaptive Resistance in Patients With Recurrent Glioblastoma","volume":"9","author":"O'Rourke","year":"2017","journal-title":"Sci Transl Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/s41392-021-00670-9","article-title":"Myeloid-Derived Suppressor Cells as Immunosuppressive Regulators and Therapeutic Targets in Cancer","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as Regulators of Tumour Immunity and Immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s40425-017-0308-4","article-title":"Inhibition of Arginase by CB-1158 Blocks Myeloid Cell-Mediated Immune Suppression in the Tumor Microenvironment","volume":"5","author":"Steggerda","year":"2017","journal-title":"J Immunother Cancer"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1800695115","article-title":"Myeloid-Derived Suppressor Cells Inhibit T Cell Activation Through Nitrating LCK in Mouse Cancers","volume":"115","author":"Feng","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nature21676","article-title":"Effective Combinatorial Immunotherapy for Castration-Resistant Prostate Cancer","volume":"543","author":"Lu","year":"2017","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12150","article-title":"Recommendations for Myeloid-Derived Suppressor Cell Nomenclature and Characterization Standards","volume":"7","author":"Bronte","year":"2016","journal-title":"Nat Commun"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0230","article-title":"Reduction of MDSCs With All-Trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas","volume":"4","author":"Long","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"B54","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2018.09.007","article-title":"Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages","volume":"175","author":"Su","year":"2018","journal-title":"Cell"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/srep15651","article-title":"Secreted Factors From Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions","volume":"5","author":"Lundholm","year":"2015","journal-title":"Sci Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0448","article-title":"Differential Effects of Depleting Versus Programming Tumor-Associated Macrophages on Engineered T Cells in Pancreatic Ductal Adenocarcinoma","volume":"7","author":"Stromnes","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001466","article-title":"Blockade of AIM2 Inflammasome or Alpha1-AR Ameliorates IL-1beta Release and Macrophage-Mediated Immunosuppression Induced by CAR-T Treatment","volume":"9","author":"Liu","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000610","article-title":"Conversion of ATP to Adenosine by CD39 and CD73 in Multiple Myeloma can be Successfully Targeted Together With Adenosine Receptor A2A Blockade","volume":"8","author":"Yang","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101225","article-title":"Adenosinergic Regulation of the Expansion and Immunosuppressive Activity of CD11b+Gr1+ Cells","volume":"187","author":"Ryzhov","year":"2011","journal-title":"J Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab"},{"key":"B61","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/s41590-019-0589-5","article-title":"CD36-Mediated Metabolic Adaptation Supports Regulatory T Cell Survival and Function in Tumors","volume":"21","author":"Wang","year":"2020","journal-title":"Nat Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-1347","article-title":"TGFbeta1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer","volume":"6","author":"Park","year":"2016","journal-title":"Cancer Discov"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.04.019","article-title":"T Cell Surveillance of Oncogene-Induced Prostate Cancer is Impeded by T Cell-Derived TGF-Beta1 Cytokine","volume":"35","author":"Donkor","year":"2011","journal-title":"Immunity"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nature14395","article-title":"Immunosuppressive Plasma Cells Impede T-Cell-Dependent Immunogenic Chemotherapy","volume":"521","author":"Shalapour","year":"2015","journal-title":"Nature"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0310","article-title":"Autocrine TGFbeta Is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment","volume":"7","author":"Gonzalez-Junca","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nature25492","article-title":"TGFbeta Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis","volume":"554","author":"Tauriello","year":"2018","journal-title":"Nature"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000676","article-title":"Inhibition of TGF-Beta-Receptor Signaling Augments the Antitumor Function of ROR1-Specific CAR T-Cells Against Triple-Negative Breast Cancer","volume":"8","author":"Stuber","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B68","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.ccr.2013.09.014","article-title":"Low-Dose Irradiation Programs Macrophage Differentiation to an iNOS(+)\/M1 Phenotype That Orchestrates Effective T Cell Immunotherapy","volume":"24","author":"Klug","year":"2013","journal-title":"Cancer Cell"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgw007","article-title":"Low Doses of Gamma Irradiation Potentially Modifies Immunosuppressive Tumor Microenvironment by Retuning Tumor-Associated Macrophages: Lesson From Insulinoma","volume":"37","author":"Prakash","year":"2016","journal-title":"Carcinogenesis"},{"key":"B70","doi-asserted-by":"publisher","first-page":"3963","DOI":"10.3390\/ijms19123963","article-title":"Preliminary Study of the Effect of Stereotactic Body Radiotherapy (SBRT) on the Immune System in Lung Cancer Patients Unfit for Surgery: Immunophenotyping Analysis","volume":"19","author":"Navarro-Martin","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.4161\/onci.28518","article-title":"Radiation Fosters Dose-Dependent and Chemotherapy-Induced Immunogenic Cell Death","volume":"3","author":"Golden","year":"2014","journal-title":"Oncoimmunology"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/nm1622","article-title":"Toll-Like Receptor 4-Dependent Contribution of the Immune System to Anticancer Chemotherapy and Radiotherapy","volume":"13","author":"Apetoh","year":"2007","journal-title":"Nat Med"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1172\/JCI138740","article-title":"Radiotherapy-Exposed CD8+ and CD4+ Neoantigens Enhance Tumor Control","volume":"131","author":"Lhuillier","year":"2021","journal-title":"J Clin Invest"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e31828298e6","article-title":"Effects of Tumor Irradiation on Host T-Regulatory Cells and Systemic Immunity in the Context of Adoptive T-Cell Therapy in Mice","volume":"36","author":"Wei","year":"2013","journal-title":"J Immunother"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2018.6","article-title":"Using Immunotherapy to Boost the Abscopal Effect","volume":"18","author":"Ngwa","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2008.10.039","article-title":"Radiation-Induced Lymphocyte Apoptosis to Predict Radiation Therapy Late Toxicity in Prostate Cancer Patients","volume":"74","author":"Schnarr","year":"2009","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.7.3760","article-title":"Differential Sensitivity of Naive and Memory CD8+ T Cells to Apoptosis In Vivo","volume":"169","author":"Grayson","year":"2002","journal-title":"J Immunol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"3959","DOI":"10.1038\/s41467-019-11906-2","article-title":"Tumor-Reprogrammed Resident T Cells Resist Radiation to Control Tumors","volume":"10","author":"Arina","year":"2019","journal-title":"Nat Commun"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.05.014","article-title":"Regulatory T Cells Shape the Differential Impact of Radiation Dose-Fractionation Schedules on Host Innate and Adaptive Antitumor Immune Defenses","volume":"111","author":"Sia","year":"2021","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1038","article-title":"Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration","volume":"24","author":"Oweida","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djz036","article-title":"STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer","volume":"111","author":"Oweida","year":"2019","journal-title":"J Natl Cancer Inst"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/286170","article-title":"Selective Depletion of Regulatory T Cell Subsets by Docetaxel Treatment in Patients With Nonsmall Cell Lung Cancer","volume":"2014","author":"Li","year":"2014","journal-title":"J Immunol Res"},{"key":"B83","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1002\/ijc.27990","article-title":"Low-Dose Gemcitabine Depletes Regulatory T Cells and Improves Survival in the Orthotopic Panc02 Model of Pancreatic Cancer","volume":"133","author":"Shevchenko","year":"2013","journal-title":"Int J Cancer"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.3390\/cancers13061440","article-title":"CTLA-4 in Regulatory T Cells for Cancer Immunotherapy","volume":"13","author":"Sobhani","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B85","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.coph.2020.07.001","article-title":"Targeting CD73 to Augment Cancer Immunotherapy","volume":"53","author":"Roh","year":"2020","journal-title":"Curr Opin Pharmacol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.3390\/biomedicines9091277","article-title":"Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development","volume":"9","author":"Rotte","year":"2021","journal-title":"Biomedicines"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1038\/s41467-017-01883-9","article-title":"DNA Double-Strand Break Repair Pathway Regulates PD-L1 Expression in Cancer Cells","volume":"8","author":"Sato","year":"2017","journal-title":"Nat Commun"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1258","article-title":"Acquired Resistance to Fractionated Radiotherapy Can be Overcome by Concurrent PD-L1 Blockade","volume":"74","author":"Dovedi","year":"2014","journal-title":"Cancer Res"},{"key":"B89","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41389-020-00257-z","article-title":"Targeting PD-L1 in Non-Small Cell Lung Cancer Using CAR T Cells","volume":"9","author":"Liu","year":"2020","journal-title":"Oncogenesis"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2310","article-title":"Extracellular Adenosine Production by Ecto-5'-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis","volume":"76","author":"Wirsdorfer","year":"2016","journal-title":"Cancer Res"},{"key":"B91","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.3390\/cancers13092105","article-title":"Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression Through A2AR-Akt-Beta-Catenin Signaling","volume":"13","author":"Jin","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00162","article-title":"Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells","volume":"10","author":"Sorrentino","year":"2019","journal-title":"Front Immunol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2826","article-title":"A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment","volume":"78","author":"Young","year":"2018","journal-title":"Cancer Res"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0449","article-title":"CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection","volume":"8","author":"Wennerberg","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B95","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1186\/s12885-020-06893-3","article-title":"CD73 Blockade Enhances the Local and Abscopal Effects of Radiotherapy in a Murine Rectal Cancer Model","volume":"20","author":"Tsukui","year":"2020","journal-title":"BMC Cancer"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0502","article-title":"CAR-T Cells Surface-Engineered With Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-Cell Hypofunction","volume":"6","author":"Siriwon","year":"2018","journal-title":"Cancer Immunol Res"},{"key":"B97","doi-asserted-by":"publisher","first-page":"3236","DOI":"10.1038\/s41467-021-23331-5","article-title":"CRISPR\/Cas9 Mediated Deletion of the Adenosine A2A Receptor Enhances CAR T Cell Efficacy","volume":"12","author":"Giuffrida","year":"2021","journal-title":"Nat Commun"},{"key":"B98","doi-asserted-by":"publisher","first-page":"3753","DOI":"10.3390\/cancers12123753","article-title":"Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients With Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study","volume":"12","author":"Mayer","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B99","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41571-020-0403-1","article-title":"TGFbeta Biology in Cancer Progression and Immunotherapy","volume":"18","author":"Derynck","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3511","article-title":"TGFbeta Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity","volume":"75","author":"Vanpouille-Box","year":"2015","journal-title":"Cancer Res"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.05.003","article-title":"Dominant-Negative TGF-Beta Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication","volume":"26","author":"Kloss","year":"2018","journal-title":"Mol Ther"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133977","article-title":"TGF-Beta Inhibition via CRISPR Promotes the Long-Term Efficacy of CAR T Cells Against Solid Tumors","volume":"5","author":"Tang","year":"2020","journal-title":"JCI Insight"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.6_suppl.125","article-title":"A Phase I Clinical Trial of PSMA-Directed\/Tgf\u03b2-Insensitive CAR-T Cells in Metastatic Castration-Resistant Prostate Cancer","volume":"39","author":"Narayan","year":"2021","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.813832\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T01:56:55Z","timestamp":1641952615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.813832\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":103,"alternative-id":["10.3389\/fimmu.2021.813832"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.813832","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]},"article-number":"813832"}}