Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis
Abstract Background Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has also been observed. The determinants of immune resistance during the malignant transformation are poorly understood. Methods Anti-PD-1 antibody was admi...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1185-0 |
| _version_ | 1818134778922139648 |
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| author | Liling Wen Huanzi Lu Qiusheng Li Qunxing Li Shuqiong Wen Dikan Wang Xi Wang Juan Fang Jun Cui Bin Cheng Zhi Wang |
| author_facet | Liling Wen Huanzi Lu Qiusheng Li Qunxing Li Shuqiong Wen Dikan Wang Xi Wang Juan Fang Jun Cui Bin Cheng Zhi Wang |
| author_sort | Liling Wen |
| collection | DOAJ |
| description | Abstract Background Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has also been observed. The determinants of immune resistance during the malignant transformation are poorly understood. Methods Anti-PD-1 antibody was administered in the 4NQO-induced carcinogenesis mouse models. The mice were then subdivided into PD-1 resistance(PD-1R) group and PD-1 sensitive(PD-1S) group according to the efficacy. The expression of PD-1 and PD-L1, and the abundance of CD3+ T cells in tumor microenvironment between the two groups was tested by immunohistochemistry. In addition, the activation and effector functions, as well as the accumulation of immunosuppressive cells and expression of immune checkpoints of T cells in the draining lymph nodes and spleen between PD-1R and PD-1S group were analyzed by flow cytometry. Results Our results showed that T cell infiltration in tumor microenvironment, effector T cell cytokine secretion and central memory T cell accumulation in peripheral lymphoid organs were all inhibited in the anti-PD-1 resistance group. Furthermore, we found that an increase of regulatory T cell (Treg) population contributed to the resistance of the anti-PD-1 therapy. Notably, TIM-3 was found to be the only immunosuppressive molecule that mediated the resistance to anti-PD-1 therapy in the oral malignant transformation model. Conclusions Our findings identified a novel mechanism that T cell dysfunction contributes to the immune resistance during the malignant transformation of the oral mucosa. This study provides new targets for improving the efficacy of immunotherapy for early stage of tumorigenesis. |
| first_indexed | 2024-12-11T09:14:02Z |
| format | Article |
| id | doaj.art-d4c168d20cfa4d9ca0d897ffe9599e19 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T09:14:02Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-d4c168d20cfa4d9ca0d897ffe9599e192022-12-22T01:13:25ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-07-0138111210.1186/s13046-019-1185-0Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesisLiling Wen0Huanzi Lu1Qiusheng Li2Qunxing Li3Shuqiong Wen4Dikan Wang5Xi Wang6Juan Fang7Jun Cui8Bin Cheng9Zhi Wang10Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityKey Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen UniversityAbstract Background Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has also been observed. The determinants of immune resistance during the malignant transformation are poorly understood. Methods Anti-PD-1 antibody was administered in the 4NQO-induced carcinogenesis mouse models. The mice were then subdivided into PD-1 resistance(PD-1R) group and PD-1 sensitive(PD-1S) group according to the efficacy. The expression of PD-1 and PD-L1, and the abundance of CD3+ T cells in tumor microenvironment between the two groups was tested by immunohistochemistry. In addition, the activation and effector functions, as well as the accumulation of immunosuppressive cells and expression of immune checkpoints of T cells in the draining lymph nodes and spleen between PD-1R and PD-1S group were analyzed by flow cytometry. Results Our results showed that T cell infiltration in tumor microenvironment, effector T cell cytokine secretion and central memory T cell accumulation in peripheral lymphoid organs were all inhibited in the anti-PD-1 resistance group. Furthermore, we found that an increase of regulatory T cell (Treg) population contributed to the resistance of the anti-PD-1 therapy. Notably, TIM-3 was found to be the only immunosuppressive molecule that mediated the resistance to anti-PD-1 therapy in the oral malignant transformation model. Conclusions Our findings identified a novel mechanism that T cell dysfunction contributes to the immune resistance during the malignant transformation of the oral mucosa. This study provides new targets for improving the efficacy of immunotherapy for early stage of tumorigenesis.http://link.springer.com/article/10.1186/s13046-019-1185-0Oral precancerous lesion (OPL)Programmed cell death 1(PD-1)Central memory T cell (Tcm)Regulatory T cell (Treg)T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) |
| spellingShingle | Liling Wen Huanzi Lu Qiusheng Li Qunxing Li Shuqiong Wen Dikan Wang Xi Wang Juan Fang Jun Cui Bin Cheng Zhi Wang Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis Journal of Experimental & Clinical Cancer Research Oral precancerous lesion (OPL) Programmed cell death 1(PD-1) Central memory T cell (Tcm) Regulatory T cell (Treg) T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) |
| title | Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis |
| title_full | Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis |
| title_fullStr | Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis |
| title_full_unstemmed | Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis |
| title_short | Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis |
| title_sort | contributions of t cell dysfunction to the resistance against anti pd 1 therapy in oral carcinogenesis |
| topic | Oral precancerous lesion (OPL) Programmed cell death 1(PD-1) Central memory T cell (Tcm) Regulatory T cell (Treg) T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) |
| url | http://link.springer.com/article/10.1186/s13046-019-1185-0 |
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