Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer
| العنوان: | Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer |
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| المؤلفون: | Kouji Matsushima, Tetsuya Nakatsura, Shigeyuki Shichino, Manami Shimomura, Hiroyasu Aoki, Makiko Yamashita, Makoto Kurachi, Haru Ogiwara, Satoru Ito, Shigehisa Kitano, Masashi Wakabayashi, Toshihiro Suzuki, Toshihiko Doi, Satoshi Ueha, Sakiko Kuroda, Kohei Shitara |
| المصدر: | Cancer Immunology Research. 9:624-636 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Repertoire, Immunology, T-cell receptor, Cell, Cancer, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monoclonal, medicine, Cancer research, Gastrointestinal cancer, Receptor, CD8 |
| الوصف: | Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood–tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer. See related Spotlight on p. 601 |
| تدمد: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-20-0989 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::b337a64efd002a123c1459cbeea8aaa5 https://doi.org/10.1158/2326-6066.cir-20-0989 |
| رقم الانضمام: | edsair.doi...........b337a64efd002a123c1459cbeea8aaa5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23266074 23266066 |
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| DOI: | 10.1158/2326-6066.cir-20-0989 |