{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:44:07Z","timestamp":1793058247134,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K18346 , 21H02995, 23K08750, 23K06782"],"award-info":[{"award-number":["23K18346 , 21H02995, 23K08750, 23K06782"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19ck0106360h0003"],"award-info":[{"award-number":["19ck0106360h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Clear cell renal cell carcinoma (ccRCC) presents a unique immunological paradox: abundant CD8\n                    <jats:sup>+<\/jats:sup>\n                    tumor-infiltrating lymphocytes (TILs) correlate with poor prognosis. To clarify their functional status and therapeutic potential, we performed single-cell transcriptomic profiling of TILs from 15 patients with ccRCC and functionally validated dominant T cell receptor (TCR) clonotypes using autologous tumor-derived organoids. Single-cell RNA sequencing revealed dynamic shifts in T cell composition, with effector and progenitor-exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells declining and terminally exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    and regulatory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells enriched in advanced tumors. Despite this exhausted phenotype, in an exploratory analysis with five patients, approximately half of the top 20 TCR clonotypes retained anti-tumor reactivity when re-expressed in non-exhausted T cells, as evidenced by TCR-T cell-mediated cytotoxicity and IFN-\u03b3 production against autologous organoids. Transcriptomic signatures enabled the development of a penalized logistic regression classifier that distinguished tumor-reactive from bystander T cells with high accuracy, with AUCs of 0.903 (training) and 0.913 (test). Cross-cancer comparison with pancreatic ductal adenocarcinoma (PDAC) datasets revealed limited generalizability, highlighting the need for cancer type-specific models. Notably, ccRCC-specific TILs exhibited mature, functionally differentiated profiles with limited proliferation, consistent with chronic antigen exposure, whereas PDAC-reactive TILs showed highly proliferative and activated phenotypes indicative of ongoing clonal expansion. Collectively, these findings suggest key features of the immune landscape in ccRCC and provide a preliminary, proof-of-concept transcriptomic framework for prioritizing candidate tumor-reactive TCRs. These insights suggest the feasibility of identifying candidate TCRs for future development of TCR-based adoptive T cell therapies in ccRCC and emphasize the importance of integrating single-cell profiling with functional analyses to refine immunotherapeutic strategies. Given the limited sample size, our results should be considered exploratory and hypothesis-generating, and future studies will be required to validate these findings in larger, independent ccRCC cohorts.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1729388","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:42:46Z","timestamp":1769668966000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Tumor-reactive TCRs within exhausted TILs reveal cancer type-specific immune landscapes in renal cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Mitsuru","family":"Komahashi","sequence":"first","affiliation":[{"name":"Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute","place":["Yokohama, Japan"]},{"name":"Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute","place":["Yokohama, 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