Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients

作者：Mate Z Nagy, Lourdes Plaza-Rojas, Justin C. Boucher, Elena V. Kostenko, Anna L Austin, Ahmad A. Tarhini, Zhihua Chen, Dongliang Du, Awino Maureiq E. Ojwang’, Joshua S. Davis, Alyssa Obermayer, Katarzyna A. Rejniak, Timothy I. Shaw, José A. Guevara-Patiño · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010153 · 被引用次数：11 · 研究领域：Cancer Immunotherapy and Biomarkers、Mathematical Biology Tumor Growth、Single-cell and spatial transcriptomics

Background In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma. Methods To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes. Results We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50–100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic ...