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The PREDICT trial examined whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) in aPDAC patients but found no association. We hypothesized that the tumor immune microenvironment (TiME) could correlate with the outcome in this trial and assessed whether tissue features were reflected in peripheral blood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PREDICT patients received 5-FU\/LV plus nanoliposomal irinotecan as second-line treatment. We stratified patients by shortest vs. longest TTF2 and analyzed 20 treatment-na\u00efve tumor tissues samples via transcriptomics and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from 82 patients collected prior to second-line therapy underwent flow cytometry and gene expression profiling. A machine learning pipeline integrated PBMC and clinical data to predict second-line outcome including external validation in 30 patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Long-TTF2 tumors exhibited an immune-active (\u201chot\u201d) TiME with cytotoxic CXCR3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      -T-cell infiltration. PBMC analysis showed that these immune features were reflected in peripheral blood after one line of treatment. A novel 7-feature PBMC-based model (\u201cTTF2Pred\u201d) accurately predicted TTF2 and overall survival, outperforming clinical or CA19-9 models and was confirmed in an external validation cohort. Long-TTF2 patients exhibited more circulating CXCR3\u207a-T-cells and plasmacytoid dendritic cells. Short-TTF2 patients had more platelet-leukocyte aggregates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>An immune-active, treatment-na\u00efve TiME predicts a better second-line outcome, and these characteristics imprinted into PBMCs obtained after one line of chemotherapy. We here first describe a minimally invasive, PBMC-based predictor of second-line outcome as a powerful prognostic tool for triaging patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT03468335 (registered March 15, 2018).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-025-02406-7","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T04:29:22Z","timestamp":1753158562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An immune responsive tumor microenvironment imprints into PBMCs and predicts outcome in advanced pancreatic cancer: lessons from the PREDICT trial"],"prefix":"10.1186","volume":"24","author":[{"given":"Anton","family":"Lahusen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred P.","family":"Lutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kirchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Albus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Kluck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meinolf","family":"Karthaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Schwarzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Siegler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kleger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Ettrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Becher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"H\u00f6fling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens T.","family":"Siveke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Budczies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Tannapfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albrecht","family":"Stenzinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis Fung-Yi","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Eiseler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"2406_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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An independent ethics committee (Ethics Committee of the Medical Association of Saarland, Faktoreistra\u00dfe 4, 66111 Saarbr\u00fccken) reviewed the study and all amendments with ethics approval number 211\/17. Written informed consent, including participation in translational research, was obtained from each patient before any study-specific medical procedure was performed.Liquid biopsy samples were collected upon informed consent including participation in translational research and stored in the Internal Medicine I Liquid Biopsy Biobank at the University Hospital Ulm, in accordance with ethics approval 67\/19 (Ethics Committee of the University of Ulm, Helmholtzstra\u00dfe 20, 89081 Ulm). The cited local ethics approval 67\/19 covers secondary use of biobank samples. We only used patients that had given their written full consent for the use of biomaterials.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"202"}}