{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:42:51Z","timestamp":1792755771231,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"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>The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response\u2019s activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1022011","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T12:04:23Z","timestamp":1667477063000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model"],"prefix":"10.3389","volume":"13","author":[{"given":"Yun","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Bertolet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hampartsoum B.","family":"Barsoumian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalini B.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denaha J.","family":"Doss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia S. Kettlun","family":"Leyton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany A.","family":"Voss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Masrorpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Leuschner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan T.","family":"Pietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahum","family":"Puebla-Osorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumil","family":"Gandhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quynh-Nhu","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Angelica","family":"Cortez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Welsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.342.6165.1432","article-title":"Breakthrough of the year 2013","volume":"342","author":"Couzin-Frankel","year":"2013","journal-title":"Cancer Immunother Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666170804143706","article-title":"Immune checkpoint inhibitors: Basics and challenges","volume":"26","author":"Li","year":"2019","journal-title":"Curr Med Chem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/471561a","article-title":"Melanoma drug wins US approval","volume":"471","author":"Ledford","year":"2011","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt291","article-title":"Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20)","volume":"24","author":"McDermott","year":"2013","journal-title":"Ann Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5238.932","article-title":"The yin and yang of T cell costimulation","volume":"270","author":"Allison","year":"1995","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni0702-611","article-title":"CTLA-4: new insights into its biological function and use in tumor immunotherapy","volume":"3","author":"Egen","year":"2002","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.cytogfr.2017.06.011","article-title":"Rationally combining immunotherapies to improve efficacy of immune checkpoint blockade in solid tumors","volume":"36","author":"Dammeijer","year":"2017","journal-title":"Cytokine Growth Factor Rev"},{"key":"B9","first-page":"4552","article-title":"Abstract 4552: Preclinical characterization of BMS-986218, a novel nonfucosylated anti\u2013CTLA-4 antibody designed to enhance antitumor activity.","volume-title":"Cancer Research","author":"Engelhardt","year":"2020"},{"key":"B10","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1158\/2326-6066.CIR-13-0013","article-title":"Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells","volume":"1","author":"Selby","year":"2013","journal-title":"Cancer Immunol Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130579","article-title":"Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma","volume":"210","author":"Simpson","year":"2013","journal-title":"J Exp Med"},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2017-SY09-01","article-title":"Abstract SY09-01: Next-generation anti-CTLA-4 antibodies","volume-title":"Cancer Research","author":"Korman","year":"2017"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00511","article-title":"Abscopal effects in Radio-Immunotherapy\u2013response analysis of metastatic cancer patients with progressive disease under anti-PD-1 immune checkpoint inhibition","volume":"10","author":"Trommer","year":"2019","journal-title":"Front Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.115.167247","article-title":"Radioimmunotherapy: from current clinical success to future industrial breakthrough","volume":"57","author":"Kraeber-Bod\u00e9r\u00e9","year":"2016","journal-title":"J Nucl Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00163","article-title":"Turning \u201ccold\u201d into \u201chot\u201d tumors\u2013opportunities and challenges for radio-immunotherapy against primary and metastatic brain cancers","volume":"9","author":"Sevenich","year":"2019","journal-title":"Front Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30326-2","article-title":"NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act. in. sarc): a multicentre, phase 2\u20133, randomised, controlled trial","volume":"20","author":"Bonvalot","year":"2019","journal-title":"Lancet Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.06.041","article-title":"Radiation therapy enhanced by NBTXR3 nanoparticles overcomes anti-PD1 resistance and evokes abscopal effects","volume":"111","author":"Hu","year":"2021","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3843","DOI":"10.2147\/IJN.S250490","article-title":"Radiotherapy-activated hafnium oxide nanoparticles produce abscopal effect in a mouse colorectal cancer model","volume":"15","author":"Zhang","year":"2020","journal-title":"Int J Nanomedicine"},{"key":"B19","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1186\/s12951-021-01163-1","article-title":"A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model","volume":"19","author":"Hu","year":"2021","journal-title":"J Nanobiotechnology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.2590","article-title":"A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers","volume":"39","author":"Shen","year":"2021","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01597","article-title":"PD-1\/PD-L1 blockade: Have we found the key to unleash the antitumor immune response","volume":"8","author":"Xu-Monette","year":"2017","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3142","article-title":"Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy","volume":"77","author":"Wang","year":"2017","journal-title":"Cancer Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3364","article-title":"MiXCR: software for comprehensive adaptive immunity profiling","volume":"12","author":"Bolotin","year":"2015","journal-title":"Nat Methods"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00022","article-title":"Immunoglobulin and T cell receptor genes: IMGT((R)) and the birth and rise of immunoinformatics","volume":"5","author":"Lefranc","year":"2014","journal-title":"Front Immunol"},{"key":"B25","article-title":"Immunarch: An r package for painless bioinformatics analysis of T-cell and b-cell immune repertoires","volume":"10","author":"Team","year":"2019","journal-title":"Nairobi: Zenodo"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu393","article-title":"Circlize implements and enhances circular visualization in r","volume":"30","author":"Gu","year":"2014","journal-title":"Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30171-8","article-title":"Optimising efficacy and reducing toxicity of anticancer radioimmunotherapy","volume":"20","author":"Deutsch","year":"2019","journal-title":"Lancet Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.08.023","article-title":"Radiation therapy and the in situ vaccination approach","volume":"108","author":"Golden","year":"2020","journal-title":"Int J Radiat Oncology Biology Phys"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S301182","article-title":"NBTXR3 radiotherapy-activated functionalized hafnium oxide nanoparticles show efficient antitumor effects across a Large panel of human cancer models","volume":"16","author":"Zhang","year":"2021","journal-title":"Int J Nanomedicine"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/1748-717X-9-150","article-title":"Hafnium oxide nanoparticles: toward an in vitro predictive biological effect","volume":"9","author":"Marill","year":"2014","journal-title":"Radiat Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2217\/fon.12.96","article-title":"Nanoscale radiotherapy with hafnium oxide nanoparticles","volume":"8","author":"Maggiorella","year":"2012","journal-title":"Future Oncol (London England)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2019.07.029","article-title":"DNA Damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS-STING pathway activation in human colorectal cancer cells","volume":"141","author":"Marill","year":"2019","journal-title":"Radiother Oncol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s12935-022-02615-w","article-title":"Radiotherapy-activated NBTXR3 nanoparticles modulate cancer cell immunogenicity and TCR repertoire","volume":"22","author":"Darmon","year":"2022","journal-title":"Cancer Cell Int"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30306-7","article-title":"Radioimmunotherapy for the treatment of head and neck cancer","volume":"20","author":"Karam","year":"2019","journal-title":"Lancet Oncol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s12916-015-0455-8","article-title":"Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis","volume":"13","author":"Bertrand","year":"2015","journal-title":"BMC Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-SITC2020.0393","article-title":"393 first-in-human phase 1\/2a study of the novel nonfucosylated anti\u2013CTLA-4 monoclonal antibody BMS-986218 \u00b1 nivolumab in advanced solid tumors: initial phase 1 results","volume":"8","author":"Friedman","year":"2020","journal-title":"J ImmunoTherapy Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0175-7","article-title":"Regulatory T cells in cancer immunosuppression\u2013implications for anticancer therapy","volume":"16","author":"Togashi","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140559","article-title":"VEGF-a modulates expression of inhibitory checkpoints on CD8+ T cells in tumors","volume":"212","author":"Voron","year":"2015","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3304","article-title":"Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer","volume":"67","author":"Hinz","year":"2007","journal-title":"Cancer Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1022011\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T12:04:33Z","timestamp":1667477073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1022011\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2022.1022011"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1022011","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]},"article-number":"1022011"}}