{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T06:06:50Z","timestamp":1784354810414,"version":"3.55.0"},"reference-count":57,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"content-version":"unspecified","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009729","name":"Ludwig Institute for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009729","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Belgian Foundation Against Cancer","award":["2010-174"],"award-info":[{"award-number":["2010-174"]}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["T\u00e9l\u00e9vie Grant 7.4538.14"],"award-info":[{"award-number":["T\u00e9l\u00e9vie Grant 7.4538.14"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Walloon Excellence in Life Sciences and Biotechnology"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,1,6]]},"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Transforming growth factor-\u03b2 (TGF\u03b2) is emerging as a promising target for cancer therapy, given its ability to promote progression of advanced tumors and to suppress anti-tumor immune responses. However, TGF\u03b2 also plays multiple roles in normal tissues, particularly during organogenesis, raising toxicity concerns about TGF\u03b2 blockade. Dose-limiting cardiovascular toxicity was observed, possibly due to the blockade of all three TGF\u03b2 isoforms. The dominant isoform in tumors is TGF\u03b21, while TGF\u03b22 and TGF\u03b23 seem to be more involved in cardiovascular development. Recent data indicated that selective targeting of TGF\u03b21 promoted the efficacy of checkpoint inhibitor anti-PD1 in transplanted preclinical tumor models, without cardiovascular toxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To further explore the therapeutic potential of isoform-specific TGF\u03b2 blockade, we developed neutralizing mAbs targeting mature TGF\u03b21 or TGF\u03b23, and tested them, in parallel with anti-panTGF\u03b2 mAb 1D11, in two preclinical models: the transplanted colon cancer model CT26, and the autochthonous melanoma model TiRP.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We observed that the blockade of TGF\u03b21, but not that of TGF\u03b23, increased the efficacy of a prophylactic cellular vaccine against colon cancer CT26. This effect was similar to pan-TGF\u03b2 blockade, and was associated with increased infiltration of activated CD8 T cells in the tumor, and reduced levels of regulatory T cells and myeloid-derived suppressor cells. In contrast, in the autochthonous TiRP melanoma model, we observed therapeutic efficacy of the TGF\u03b21-specific mAb as a single agent, while the TGF\u03b23 mAb was inactive. In this model, the anti-tumor effect of TGF\u03b21 blockade was tumor intrinsic rather than immune mediated, as it was also observed in T-cell depleted mice. Mechanistically, TGF\u03b21 blockade increased mouse survival by delaying the phenotype switch, akin to epithelial-to-mesenchymal transition (EMT), which transforms initially pigmented tumors into highly aggressive unpigmented tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results confirm TGF\u03b21 as the relevant isoform to target for cancer therapy, not only in combination with checkpoint inhibitors, but also with other immunotherapies such as cancer vaccines. Moreover, TGF\u03b21 blockade can also act as a monotherapy, through a tumor-intrinsic effect blocking the EMT-like transition. Because human melanomas that resist therapy often express a gene signature that links TGF\u03b21 with EMT-related genes, these results support the clinical development of TGF\u03b21-specific mAbs in melanoma.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001798","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T10:53:44Z","timestamp":1614336824000},"page":"e001798","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["TGF\u03b21 neutralization displays therapeutic efficacy through both an immunomodulatory and a non-immune tumor-intrinsic mechanism"],"prefix":"10.1136","volume":"9","author":[{"given":"Stefania","family":"Can\u00e8","sequence":"first","affiliation":[{"name":"Ludwig Institute for Cancer Research, De Duve Institute, Brussels, Belgium"},{"name":"de Duve Institute, UCLouvain, Brussels, Belgium"},{"name":"Department of Medicine, Immunology Section, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Van Snick","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, De Duve Institute, Brussels, Belgium"},{"name":"de Duve Institute, UCLouvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Uyttenhove","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, De Duve Institute, Brussels, Belgium"},{"name":"de Duve Institute, UCLouvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Pilotte","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, De Duve Institute, Brussels, Belgium"},{"name":"de Duve Institute, UCLouvain, Brussels, Belgium"},{"name":"WELBIO, UCLouvain, Brussels, 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