{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:04:07Z","timestamp":1791227047711,"version":"4.1.0"},"posted":{"date-parts":[[2025,12,29]]},"group-title":"Immunology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Immune checkpoint inhibitors (ICIs) elicit durable responses in only a subset of patients with solid tumors, underscoring the need to define the cellular architectures that govern effective antitumor immunity. Here we identify a spatially organized multicellular immune unit comprising macrophages, cDC1s, CD4\u207a T-cells, and CD8\u207a T-cells that emerges in response to anti-CTLA-4 or dual checkpoint blockade. We term these structures\n                  <jats:italic>tetrads<\/jats:italic>\n                  . Using multiplexed imaging and spatial transcriptomics in mouse and human tumors, we show that tetrads assemble early during immune priming, depend on the ICOS\u2013ICOSL pathway, and are enriched for ICOS\u207a Th1-like CD4\u207a T cells and ICOSL\n                  <jats:sup>high<\/jats:sup>\n                  cDC1s. CD8\u207a T-cells within tetrads exhibit an activated, non-terminally differentiated state, while tetrad-associated macrophages display an interferon-\u03b3\u2013responsive program that sustains CD8\u207a T-cell function and prevents dysfunction. Functionally, ICOSL\u207a cDC1s are required for tumor eradication\n                  <jats:italic>in vivo<\/jats:italic>\n                  . In patients with bladder cancer treated with neoadjuvant dual checkpoint blockade, tetrad, but not triad or dyad formation correlates with clinical response. These findings establish tetrads as a fundamental cellular unit coordinating antitumor immunity and responsiveness to ICIs.\n                <\/jats:p>","DOI":"10.64898\/2025.12.24.696419","type":"posted-content","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T19:20:25Z","timestamp":1767036025000},"source":"Crossref","is-referenced-by-count":3,"title":["Macrophage-Dendritic Cell-T-Cell Tetrads Orchestrate Antitumor Immunity and Response to Checkpoint Blockade"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4793-0120","authenticated-orcid":false,"given":"Mehdi","family":"Chaib","sequence":"first","affiliation":[{"name":"Department of Immunology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-8812","authenticated-orcid":false,"given":"Muhammad","family":"Aminu","sequence":"additional","affiliation":[{"name":"Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-6752","authenticated-orcid":false,"given":"Shelley","family":"Herbrich","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahshid","family":"Arabi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3242-0515","authenticated-orcid":false,"given":"Yue","family":"Xuan","sequence":"additional","affiliation":[{"name":"Department of Immunology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7252-1126","authenticated-orcid":false,"given":"Akshay","family":"Basi","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Biology & Malignancy, Division of Cancer Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7857-179X","authenticated-orcid":false,"given":"Anna","family":"Casasent","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Biology & Malignancy, Division of Cancer Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7282-6258","authenticated-orcid":false,"given":"Marc D.","family":"Macaluso","sequence":"additional","affiliation":[{"name":"Immunotherapy Platform, James P. 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