{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:16:24Z","timestamp":1788009384934,"version":"build-2784847793"},"posted":{"date-parts":[[2026,6,2]]},"group-title":"Immunology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["K08CA237732"],"award-info":[{"award-number":["K08CA237732"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21DE031072"],"award-info":[{"award-number":["R21DE031072"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R01DE032371"],"award-info":[{"award-number":["1R01DE032371"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R01DE032865"],"award-info":[{"award-number":["1R01DE032865"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5T32CA009547-38"],"award-info":[{"award-number":["5T32CA009547-38"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5K12CA167540-15"],"award-info":[{"award-number":["5K12CA167540-15"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00kbbk236","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/052nngb38","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007338","name":"Barnes-Jewish Hospital Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007338","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  T cells adopt diverse states in human disease, with tumor-specific CD8 T cells serving as the quintessential example. These cells are critical for immunotherapy response, yet acquire hypofunctional states of exhaustion that impair treatment efficacy. While significant heterogeneity is observed among exhausted CD8 T cells (T\n                  <jats:sub>EX<\/jats:sub>\n                  ), the mechanisms directing their unique phenotypes remain unresolved, limiting our efforts to augment T\n                  <jats:sub>EX<\/jats:sub>\n                  cell function. Here, we profile T\n                  <jats:sub>EX<\/jats:sub>\n                  cells in human head and neck squamous cell carcinoma (HNSCC) tumors and define a major mechanism regulating their cell state. With single-cell RNA and T cell receptor (TCR) sequencing of 106,667 tumor-infiltrating CD8 T cells, we define and validate three fundamental T\n                  <jats:sub>EX<\/jats:sub>\n                  subsets, each harboring dominant clonotypes: a progenitor subset (T\n                  <jats:sub>PEX<\/jats:sub>\n                  ) and two\n                  <jats:italic>intra<\/jats:italic>\n                  -tumoral populations marked by intermediate (T\n                  <jats:sub>EX-int<\/jats:sub>\n                  ) or high expression of inhibitory receptors, including killer cell lectin-like receptors, such as\n                  <jats:italic>KLRC1<\/jats:italic>\n                  \/NKG2A (T\n                  <jats:sub>EX-KLR<\/jats:sub>\n                  ). Using an\n                  <jats:italic>in vitro<\/jats:italic>\n                  model, we show that TCR avidity-dependent NFAT signaling governs an axis between the T\n                  <jats:sub>EX-int<\/jats:sub>\n                  and T\n                  <jats:sub>EX-KLR<\/jats:sub>\n                  states across human cancers, with high-avidity signaling driving the T\n                  <jats:sub>EX-KLR<\/jats:sub>\n                  state. Additionally, we uncover that interleukin-12 signaling selectively antagonizes high-avidity T\n                  <jats:sub>EX-KLR<\/jats:sub>\n                  -specific genes, despite broadly potentiating activation and cytotoxicity. Finally, we find that T\n                  <jats:sub>EX-int<\/jats:sub>\n                  and T\n                  <jats:sub>EX-KLR<\/jats:sub>\n                  cells are associated with anti-PD-1 response in HNSCC, with both of these cell types enriched near viable cancer cells following treatment. Together, these findings reveal that TCR avidity orchestrates tumor-infiltrating T\n                  <jats:sub>EX<\/jats:sub>\n                  cell states through NFAT signaling \u2013 a tunable axis that may be targeted to improve T\n                  <jats:sub>EX<\/jats:sub>\n                  cell function.\n                <\/jats:p>","DOI":"10.64898\/2026.05.29.728765","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:40:14Z","timestamp":1780465214000},"source":"Crossref","is-referenced-by-count":0,"title":["High-avidity TCR signaling drives an NKG2A-positive CD8 T cell exhaustion state in human tumors"],"prefix":"10.64898","author":[{"given":"Riley D.Z.","family":"Mullins","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse M.","family":"Zaretsky","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Stoller","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Porter","family":"Bischoff","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Marie","family":"Egloff","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Huffman","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Ramadan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna","family":"Ramadan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Ley","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Schwetye","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Miller","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"De Los Santos","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Apicelli","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil","family":"Rammohan","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wade","family":"Thorstad","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Oppelt","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan J.","family":"Knapp","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Auberle","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyong","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Buchman","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Bur","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Wahle","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason T.","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan S.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik","family":"Pipkorn","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Zolkind","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Harbison","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Egawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Oncology, Section of Cellular Therapies, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robi D.","family":"Mitra","sequence":"additional","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana D.","family":"Karam","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Adkins","sequence":"additional","affiliation":[{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravindra","family":"Uppaluri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth V.","family":"Puram","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA"},{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026082905450679000_2026.05.29.728765v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32591-7"},{"key":"2026082905450679000_2026.05.29.728765v2.2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adf4968"},{"key":"2026082905450679000_2026.05.29.728765v2.3","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1158\/1078-0432.CCR-21-3351","article-title":"Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local\u2013Regionally Advanced Head and Neck Squamous Cell CarcinomaNeoadjuvant and Adjuvant Pembrolizumab in Resected HNSCC","volume":"28","year":"2022","journal-title":"Clin. 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