Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer
Background Anti-PD-1(L1) therapies are less efficacious in patients with EGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.Methods The characteristics of T cells in EGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-12-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/12/e005436.full |
| _version_ | 1797789469102833664 |
|---|---|
| author | Lei Cheng Caicun Zhou Tao Jiang Fei Zhou Shengxiang Ren Hongcheng Liu Xinyu Liu Xiaoxia Chen Xuefei Li Chao Zhao Meng Qiao Haowei Wang Yijun Jia |
| author_facet | Lei Cheng Caicun Zhou Tao Jiang Fei Zhou Shengxiang Ren Hongcheng Liu Xinyu Liu Xiaoxia Chen Xuefei Li Chao Zhao Meng Qiao Haowei Wang Yijun Jia |
| author_sort | Lei Cheng |
| collection | DOAJ |
| description | Background Anti-PD-1(L1) therapies are less efficacious in patients with EGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.Methods The characteristics of T cells in EGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. In vitro restimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic EGFRL858R mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism in vivo.Results EGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells in EGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in EGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonous EGFRL858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in EGFR-mutated lung tumors.Conclusions Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells in EGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in EGFR-mutated tumors. |
| first_indexed | 2024-03-13T01:51:06Z |
| format | Article |
| id | doaj.art-02ad2eaf1d0540c5beaa16d9fad080d8 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-13T01:51:06Z |
| publishDate | 2022-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-02ad2eaf1d0540c5beaa16d9fad080d82023-07-02T12:00:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-12-01101210.1136/jitc-2022-005436Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancerLei Cheng0Caicun Zhou1Tao Jiang2Fei Zhou3Shengxiang Ren4Hongcheng Liu5Xinyu Liu6Xiaoxia Chen7Xuefei Li8Chao Zhao9Meng Qiao10Haowei Wang11Yijun Jia12Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People`s Republic of ChinaBackground Anti-PD-1(L1) therapies are less efficacious in patients with EGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.Methods The characteristics of T cells in EGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. In vitro restimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic EGFRL858R mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism in vivo.Results EGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells in EGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in EGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonous EGFRL858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in EGFR-mutated lung tumors.Conclusions Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells in EGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in EGFR-mutated tumors.https://jitc.bmj.com/content/10/12/e005436.full |
| spellingShingle | Lei Cheng Caicun Zhou Tao Jiang Fei Zhou Shengxiang Ren Hongcheng Liu Xinyu Liu Xiaoxia Chen Xuefei Li Chao Zhao Meng Qiao Haowei Wang Yijun Jia Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer Journal for ImmunoTherapy of Cancer |
| title | Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer |
| title_full | Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer |
| title_fullStr | Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer |
| title_full_unstemmed | Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer |
| title_short | Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer |
| title_sort | interleukin 10 induces expression of cd39 on cd8 t cells to potentiate anti pd1 efficacy in egfr mutated non small cell lung cancer |
| url | https://jitc.bmj.com/content/10/12/e005436.full |
| work_keys_str_mv | AT leicheng interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT caicunzhou interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT taojiang interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT feizhou interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT shengxiangren interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT hongchengliu interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT xinyuliu interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT xiaoxiachen interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT xuefeili interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT chaozhao interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT mengqiao interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT haoweiwang interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer AT yijunjia interleukin10inducesexpressionofcd39oncd8tcellstopotentiateantipd1efficacyinegfrmutatednonsmallcelllungcancer |