Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma
| العنوان: | Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma |
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| المؤلفون: | Kazuaki Sawada, Kazuhiro Kakimi, Tetsushi Murakami, Toshiaki Shinojima, Tsukasa Masuda, Keishiro Fukumoto, Nobuyuki Tanaka, Takeshi Imamura, Tatsuhiko Tsunoda, Kimiharu Takamatsu, Ryuichi Mizuno, Mototsugu Oya, Shuji Mikami, Kyohei Hakozaki |
| المصدر: | Cancer Immunology, Immunotherapy. 70:3001-3013 |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Pathology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, FOXP3, Immunotherapy, medicine.disease, Malignancy, Oncology, Renal cell carcinoma, Immunology and Allergy, Medicine, Immunohistochemistry, Cytotoxic T cell, business, Clear cell, CD8 |
| الوصف: | Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39-) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39- T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC. |
| تدمد: | 1432-0851 0340-7004 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::80fc2ce4e28c04cca0c0c80863ef1faeTest https://doi.org/10.1007/s00262-021-03006-2Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi...........80fc2ce4e28c04cca0c0c80863ef1fae |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14320851 03407004 |
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