期刊
CARCINOGENESIS
卷 42, 期 6, 页码 891-902出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgab035
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资金
- National Natural Science Foundation of China [81771086, 81470747, 81972551]
- China Postdoctoral Science Foundation [2019T120863]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2019-I2M-5-004]
T-cell exhaustion plays a crucial role in oral carcinogenesis, and PD-1 blockade can prevent the progression of oral cancer.
Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the head and neck with a poor prognosis. Oral cancer development is a multistep process involving carcinogenesis. Though significant advances in cancer immunotherapy over the years, there is lack of evidence for T-cell exhaustion during oral carcinogenesis. Clinical specimens from healthy donors and patients diagnosed with oral leukoplakia (OLK) or OSCC were collected for immunohistochemical staining with PD-L1, CD86, CD8, PD-1 and CTLA-4 antibodies. Meanwhile, chemically induced mouse models of oral carcinogenesis were constructed with 4-nitroquinolone-N-oxide induction. Exhaustion status of T cells was measured by flow cytometiy for spleens and by multiplex immunohistochemistry for formalin-fixed paraffin-embedded lesions in multiple stages of oral carcinogenesis. The efficacy of PD-1 blockade with or without cisplatin treatment was evaluated on the mice in precancerous and OSCC stages. We observed higher expression of PD-1 in the human OLK and OSCC tissues compared with the normal, while low expression CTLA-4 in all oral mucosa tissues. Animal experiments showed that the exhausted CD4(+) T cells existed much earlier than exhausted CD8(+) T cells, and an increased ratio of stem-like exhausted T cells and partially exhausted T cells were detected in the experimental groups. Besides, the expression of immune checkpoint markers (PDCD1, CTLA4 and HAVCR2) was strongly positively correlated with cytokines (IFNG and IL-2). In summary, T-cell exhaustion plays a vital role in oral carcinogenesis, and PD-1 blockade can prevent the progression of oral carcinogenesis.
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