{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:16Z","timestamp":1792787296227,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,8,31]],"date-time":"2020-08-31T00:00:00Z","timestamp":1598832000000},"content-version":"unspecified","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHI505\/6-1"],"award-info":[{"award-number":["SCHI505\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BIU Phase II grant from the Boehringer Ingelheim and Ulm University Biocenter","award":["TP I3"],"award-info":[{"award-number":["TP I3"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,7,30]]},"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Many cancer cells express a major histocompatibility complex class I low\/ programmed cell death 1 ligand 1 positive (MHC-I\n                      <jats:sup>lo<\/jats:sup>\n                      \/PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      ) cell surface profile. For immunotherapy, there is, thus, an urgent need to restore presentation competence of cancer cells with defects in MHC-I processing\/presentation combined with immune interventions that tackle the tumor-initiated PD-L1\/PD-1 signaling axis. Using pancreatic ductal adenocarcinoma cells (PDACCs) as a model, we here explored if (and how) expression\/processing of tumor antigens via transporters associated with antigen processing (TAP) affects priming of CD8 T cells in PD-1\/PD-L1-competent\/-deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated tumor antigen-expressing vectors, immunized TAP-competent\/-deficient mice and determined de novo primed CD8 T-cell frequencies by flow cytometry. Similarly, we explored the antigenicity and PD-L1\/PD-1 sensitivity of PDACCs versus interferon-\u03b3 (IFN-\u03b3)-treated PDACCs in PD-1\/PD-L1-competent\/deficient mice. The IFN-\u03b3-induced effects on gene and cell surface expression profiles were determined by microarrays and flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified two antigens (cripto-1 and an endogenous leukemia virus-derived gp70) that were expressed in the\n                      <jats:italic>Endoplasmic Reticulum<\/jats:italic>\n                      (ER) of PDACCs and induced CD8 T-cell responses either independent (Cripto-1:K\n                      <jats:sup>b<\/jats:sup>\n                      \/Cr\n                      <jats:sub>16-24<\/jats:sub>\n                      ) or dependent (gp70:K\n                      <jats:sup>b<\/jats:sup>\n                      \/p15E) on TAP by DNA immunization. IFN-\u03b3-treatment of PDACCs in vitro upregulated MHC-I- and TAP- but also PD-L1-expression. Mechanistically, PD-L1\/PD-1 signaling was superior to the reconstitution of MHC-I presentation competence, as subcutaneously transplanted IFN-\u03b3-treated PDACCs developed tumors in C57BL\/6J and PD-L1\n                      <jats:sup>-\/-<\/jats:sup>\n                      but not in PD-1\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Using PDACCs, irradiated at day 3 post-IFN-\u03b3-treatment or PD-L1 knockout PDACCs as vaccines, we could selectively bypass upregulation of PD-L1, preferentially induce TAP-dependent gp70:K\n                      <jats:sup>b<\/jats:sup>\n                      \/p15E-specific CD8 T cells associated with a weakened PD-1\n                      <jats:sup>+<\/jats:sup>\n                      exhaustion phenotype and reject consecutively injected tumor transplants in C57BL\/6J mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The IFN-\u03b3-treatment protocol is attractive for cell-based immunotherapies, because it restores TAP-dependent antigen processing in cancer cells, facilitates priming of TAP-dependent effector CD8 T-cell responses without additional check point inhibitors and could be combined with genetic vaccines that complement priming of TAP-independent CD8 T cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2020-000692","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T02:35:17Z","timestamp":1598927717000},"page":"e000692","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["IFN-\u03b3 treatment protocol for MHC-I\n                    <sup>lo<\/sup>\n                    \/PD-L1\n                    <sup>+<\/sup>\n                    pancreatic tumor cells selectively restores their TAP-mediated presentation competence and CD8 T-cell priming potential"],"prefix":"10.1136","volume":"8","author":[{"given":"Katja","family":"Stifter","sequence":"first","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Krieger","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Ruths","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Gout","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhanie","family":"Mulaw","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Lechel","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kleger","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wagner","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-8091","authenticated-orcid":false,"given":"Reinhold","family":"Schirmbeck","sequence":"additional","affiliation":[{"name":"Internal Medicine I, University Hospital Ulm, Ulm, 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