{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T19:32:55Z","timestamp":1777663975371,"version":"3.51.4"},"reference-count":49,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"unspecified","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["194\/18"],"award-info":[{"award-number":["194\/18"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"publisher","award":["2018-2020"],"award-info":[{"award-number":["2018-2020"]}],"id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["771112"],"award-info":[{"award-number":["771112"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,2,14]]},"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Immune checkpoint inhibitors (ICIs) have made a paradigm shift in clinical oncology due to unprecedented long-term remissions. However, only a small proportion of patients respond to ICI therapy. It is, therefore, essential to understand the mechanisms driving therapy resistance and to develop strategies for increasing response rates. We previously demonstrated that in response to various cancer treatment modalities, the host activates a range of biological processes that promote tumor regrowth and metastasis. Here, we characterize the host-mediated response to ICI therapy, and investigate its contribution to therapy resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Tumor cell migration, invasion and motility were assessed in the presence of plasma from ICI-treated mice and patients. Immune cell composition in peripheral blood and tumors of ICI-treated mice was assessed by flow and mass cytometry. Plasma host factors driving tumor aggressiveness were identified by proteomic profiling, followed by bioinformatic analysis. The therapeutic effect of inhibiting host-mediated processes in ICI-treated mice was assessed in a tumor model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Tumor cells exhibit enhanced migratory and invasive properties in vitro on exposure to plasma from anti-PD1-treated mice. Moreover, mice intravenously injected with plasma-exposed tumor cells display increased metastatic burden and mortality rate in comparison to control arms. Furthermore, tumors from anti-PD1-treated mice as well as Matrigel plugs containing plasma from anti-PD1-treated mice are highly infiltrated with immune cell types associated with both antitumor and protumor activity. These collective findings suggest that anti-PD1 treatment induces a systemic host response that potentially counteracts the drug\u2019s therapeutic activity. Proteomic profiling of plasma from anti-PD1-treated mice reveals an activation of multiple biological pathways associated with tumor aggressiveness. Consequently, blocking IL-6, one of the key drivers of the identified biological pathways, counteracts ICI-induced metastatic properties in vitro and improves ICI treatment efficacy in vivo. Lastly, plasma samples from ICI-treated non-small cell lung cancer patients differentially affect tumor cell aggressiveness in vitro, with enhanced tumor cell motility correlating with a worse clinical outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ICI therapy induces host-mediated processes that contribute to therapy resistance. Identification and analysis of such processes may lead to the discovery of biomarkers for clinical response and strategies for overcoming therapy resistance.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001996","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T10:51:22Z","timestamp":1615459882000},"page":"e001996","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Host response to immune checkpoint inhibitors contributes to tumor aggressiveness"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct03999749","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Irina","family":"Khononov","sequence":"first","affiliation":[{"name":"Rappaport Faculty of Medicine, Rappaport Technion Integrated Cancer Center, Technion Israel Institute of Technology, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eyal","family":"Jacob","sequence":"additional","affiliation":[{"name":"OncoHost LTD, Binyamina, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Fremder","sequence":"additional","affiliation":[{"name":"OncoHost LTD, Binyamina, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nili","family":"Dahan","sequence":"additional","affiliation":[{"name":"OncoHost LTD, Binyamina, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Harel","sequence":"additional","affiliation":[{"name":"OncoHost LTD, Binyamina, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziv","family":"Raviv","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Rappaport Technion Integrated Cancer Center, Technion Israel Institute of Technology, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-0828","authenticated-orcid":false,"given":"Boris","family":"Krastev","sequence":"additional","affiliation":[{"name":"Clinic of Medical Oncology, MHAT Hospital for Women Health Nadezhda, Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-3895","authenticated-orcid":false,"given":"Yuval","family":"Shaked","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Rappaport Technion Integrated Cancer Center, Technion Israel Institute of Technology, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"2025100307464158000_9.3.e001996.1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3909"},{"key":"2025100307464158000_9.3.e001996.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"2025100307464158000_9.3.e001996.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4358"},{"key":"2025100307464158000_9.3.e001996.4","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1093\/neuonc\/nox025","article-title":"Is more better? 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