{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T00:36:06Z","timestamp":1794270966042,"version":"4.9.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While immune checkpoint blockade has transformed the landscape of cancer therapy, variability in patient responses constrains its therapeutic potential. Tumor-specific stem-like T (TSL) cells sustain durable immunity through self-renewal and differentiation. However, upstream regulators of TSL cells generation remain elusive, and direct evidence is still lacking regarding whether na\u00efve tumor-specific T cell precursor frequency influences TSL cells pool establishment and immunotherapy response. This study aims to clarify the direct causal relationship between this precursor frequency and the number of TSL cells in tumor-draining lymph nodes, as well as the efficacy of anti-PD-L1 therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We initially constructed a novel bone marrow cell chimeric model. Specifically, recipient mice of the wild-type C57BL\/6 strain were subjected to lethal irradiation, after which they received intravenous adoptive transfer of a cell suspension (5 \u00d7 10\n                      <jats:sup>7<\/jats:sup>\n                      cells) comprising a blend of bone marrow cells derived from OT-I mice and wild-type mice in varying proportions. Subsequently, a subcutaneous transplanted tumor model was established by inoculating B16-OVA melanoma cells expressing the OVA antigen. Over the course of tumor progression, we evaluated tumor growth dynamics, mice survival outcomes, and T cell within the tumor-draining lymph nodes (TDLNs). Thereafter, we evaluated whether this divergence in precursor frequency of antigen-specific T cells modulates the efficacy of anti-PD-1 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The results of the bone marrow chimeric model demonstrated that: different precursor frequencies of antigen-specific T cell s significantly affect the abundance of stem-like T cells in the TDLNs of tumor-bearing mice. A higher precursor frequency of antigen-specific T cell could significantly suppress tumor growth and prolong the survival time of the mice. In the group with a higher precursor frequency, anti-PD-1 therapy effectively inhibited tumor growth, leading to long-term survival of the mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study provides the first direct\n                      <jats:italic>in vivo<\/jats:italic>\n                      evidence that the initial precursor frequency of tumor-antigen-specific T cell influences the stem-like T cell pool in TDLNs and thereby the efficacy of anti-PD-1 immunotherapy. This finding reveals a key upstream mechanism of response heterogeneity and offers a strategic rationale for overcoming ICB resistance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1771474","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:22:07Z","timestamp":1769577727000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Antigen-specific T Cell precursor frequency influences the proliferation of stem-like T Cells in tumor-draining lymph nodes and anti-tumor immune responses"],"prefix":"10.3389","volume":"13","author":[{"given":"Liangnian","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaijing","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of First Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine","place":["Nanjing, Jiangsu, China"]},{"name":"College of First Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine","place":["Nanjing, Jiangsu, China"]},{"name":"College of First Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]},{"name":"State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eadf4726","DOI":"10.1126\/sciimmunol.adf4726","article-title":"Architects of immunity: how dendritic cells shape CD8(+) T cell fate in cancer","volume":"10","author":"Bhandarkar","year":"2025","journal-title":"Sci. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.immuni.2017.01.003","article-title":"CD8(+) T cells orchestrate pDC-XCR1(+) dendritic cell spatial and functional cooperativity to optimize priming","volume":"46","author":"Brewitz","year":"2017","journal-title":"Immunity"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4996","DOI":"10.1016\/j.cell.2021.08.020","article-title":"Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors","volume":"184","author":"Burger","year":"2021","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41590-024-01792-2","article-title":"Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy","volume":"25","author":"Chen","year":"2024","journal-title":"Nat. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"eabg7836","DOI":"10.1126\/sciimmunol.abg7836","article-title":"A reservoir of stem-like CD8(+) T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response","volume":"6","author":"Connolly","year":"2021","journal-title":"Sci. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.immuni.2022.03.006","article-title":"Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches","volume":"55","author":"Dahling","year":"2022","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.trecan.2023.09.006","article-title":"The tumor-draining lymph node as a reservoir for systemic immune surveillance","volume":"10","author":"Delclaux","year":"2024","journal-title":"Trends Cancer"},{"key":"B8","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1084\/jem.20050732","article-title":"Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells","volume":"202","author":"Gattinoni","year":"2005","journal-title":"J. Exp. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/s41568-023-00615-0","article-title":"Stem-like exhausted and memory CD8(+) T cells in cancer","volume":"23","author":"Gebhardt","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.trecan.2022.12.005","article-title":"T cell-independent abscopal responses to radiotherapy","volume":"9","author":"Guilbaud","year":"2023","journal-title":"Trends Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e20211574","DOI":"10.1084\/jem.20211574","article-title":"TGF-beta regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection","volume":"219","author":"Hu","year":"2022","journal-title":"J. Exp. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1016\/j.cell.2022.09.020","article-title":"The primordial differentiation of tumor-specific memory CD8(+) T cells as bona fide responders to PD-1\/PD-L1 blockade in draining lymph nodes","volume":"185","author":"Huang","year":"2022","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"eadr3930","DOI":"10.1126\/scitranslmed.adr3930","article-title":"Depletion of plasmacytoid dendritic cells rescues HIV-reactive stem-like CD8(+) T cells during chronic HIV-1 infection","volume":"17","author":"Li","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.immuni.2015.12.018","article-title":"Clonal abundance of tumor-specific CD4(+) T cells potentiates efficacy and alters susceptibility to exhaustion","volume":"44","author":"Malandro","year":"2016","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1126\/science.aaf1490","article-title":"Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade","volume":"351","author":"McGranahan","year":"2016","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/j.immuni.2008.04.010","article-title":"Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection","volume":"28","author":"Obar","year":"2008","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.7150\/thno.88864","article-title":"Hypofractionated radiotherapy combined with lenalidomide improves systemic antitumor activity in mouse solid tumor models","volume":"14","author":"Onyshchenko","year":"2024","journal-title":"Theranostics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.immuni.2022.12.002","article-title":"CD8(+) T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor","volume":"56","author":"Prokhnevska","year":"2023","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1084\/jem.20081382","article-title":"Self-antigen-specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response","volume":"206","author":"Rizzuto","year":"2009","journal-title":"J. Exp. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1016\/j.immuni.2021.08.026","article-title":"Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1(+) CD8(+) T cells in tumor-draining lymph nodes","volume":"54","author":"Schenkel","year":"2021","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1016\/j.cell.2023.03.006","article-title":"Immune checkpoint therapy-current perspectives and future directions","volume":"186","author":"Sharma","year":"2023","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","article-title":"Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy","volume":"50","author":"Siddiqui","year":"2019","journal-title":"Immunity"},{"key":"B23","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1111\/imm.12033","article-title":"Differential requirements of CD4(+) T-cell signals for effector cytotoxic T-lymphocyte (CTL) priming and functional memory CTL development at higher CD8(+) T-cell precursor frequency","volume":"138","author":"Umeshappa","year":"2013","journal-title":"Immunology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev-immunol-070621-030155","article-title":"Resistance mechanisms to Anti-PD cancer immunotherapy","volume":"40","author":"Vesely","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/s41590-022-01219-w","article-title":"Stem-like' precursors are the fount to sustain persistent CD8(+) T cell responses","volume":"23","author":"Zehn","year":"2022","journal-title":"Nat. Immunol."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1771474\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:13:57Z","timestamp":1771924437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1771474\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":26,"alternative-id":["10.3389\/fmolb.2026.1771474"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1771474","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]},"article-number":"1771474"}}