{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:55:07Z","timestamp":1788245707694,"version":"build-2803163510"},"reference-count":54,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"unspecified","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013030","name":"William and Ella Owens Medical Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100013030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-20-1-0757"],"award-info":[{"award-number":["W81XWH-20-1-0757"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA205965"],"award-info":[{"award-number":["CA205965"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,12,31]]},"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Anti-programmed death-ligand 1 (\u03b1PD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in &lt;30% of patients. Interleukin (IL)-2\/\u03b1IL-2 complexes (IL-2c) that preferentially target IL-2 receptor \u03b2 (CD122) augment CD8<jats:sup>+<\/jats:sup> antitumor T cells known to improve \u03b1PD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement \u03b1PD-L1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We studied mechanisms of IL-2c and \u03b1PD-L1 efficacy using PD-L1<jats:sup>+<\/jats:sup> mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>IL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to \u03b1PD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8<jats:sup>+<\/jats:sup> T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas \u03b3\u03b4 T cells, not reported to contribute to \u03b1PD-L1 efficacy, were indispensable for IL-2c efficacy there. \u03b1PD-L1 responsiveness in bladder required conventional T cells as expected, but not \u03b3\u03b4 T cells, altogether defining distinct mechanisms for IL-2c and \u03b1PD-L1 efficacy. \u03b3\u03b4 T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and\/or tumor-specific \u03b3\u03b4 T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral \u03b3\u03b4 T cell content, activation status, and specific \u03b3\u03b4 T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor \u03b1PD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8<jats:sup>+<\/jats:sup> T cells but not \u03b3\u03b4 T cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mechanistic insights into differential IL-2c and \u03b1PD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into \u03b3\u03b4 T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus \u03b1PD-L1 to treat refractory lung metastases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-002051","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T13:34:56Z","timestamp":1618320896000},"page":"e002051","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from \u03b1PD-L1 and include tissue-selective \u03b3\u03b4 T cell activation"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-5809","authenticated-orcid":false,"given":"Ryan Michael","family":"Reyes","sequence":"first","affiliation":[{"name":"South Texas Medical Scientist Training Program, University of Texas Health San Antonio, San Antonio, 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