1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells
Background Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vita...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003477.full |
| _version_ | 1797771628998819840 |
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| author | Peng Li Hua Zhang Xiao Wang Biyun Chen Ke Li Zhinan Yin Xinhai Zhu Guangchao Cao Ruan Wu Wenhui Yuan Guodong Sun Xichun Xia Ligong Lu Yunfei Gao |
| author_facet | Peng Li Hua Zhang Xiao Wang Biyun Chen Ke Li Zhinan Yin Xinhai Zhu Guangchao Cao Ruan Wu Wenhui Yuan Guodong Sun Xichun Xia Ligong Lu Yunfei Gao |
| author_sort | Peng Li |
| collection | DOAJ |
| description | Background Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.Methods Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5–2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells.Results We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC.Conclusions Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.Trial registration number ChiCTR2100051135. |
| first_indexed | 2024-03-12T21:39:24Z |
| format | Article |
| id | doaj.art-5627e92f9cd14fcaae7daf2d0f898d04 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:39:24Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-5627e92f9cd14fcaae7daf2d0f898d042023-07-27T05:25:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-0034771α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cellsPeng Li0Hua Zhang1Xiao Wang2Biyun Chen3Ke Li4Zhinan Yin5Xinhai Zhu6Guangchao Cao7Ruan Wu8Wenhui Yuan9Guodong Sun10Xichun Xia11Ligong Lu12Yunfei Gao13Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaInner Mongolia People’s Hospital, ChinaSun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaDepartment of Infectious Disease, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaDepartment of Oncology, First Affiliated Hospital, Jinan University, Jinan University, Guangzhou, Guangdong, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaAnhui Provincial Center for Disease Control and Prevention, Hefei, Anhui, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaDepartment of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People`s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, ChinaBackground Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.Methods Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5–2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells.Results We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC.Conclusions Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.Trial registration number ChiCTR2100051135.https://jitc.bmj.com/content/10/3/e003477.full |
| spellingShingle | Peng Li Hua Zhang Xiao Wang Biyun Chen Ke Li Zhinan Yin Xinhai Zhu Guangchao Cao Ruan Wu Wenhui Yuan Guodong Sun Xichun Xia Ligong Lu Yunfei Gao 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells Journal for ImmunoTherapy of Cancer |
| title | 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells |
| title_full | 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells |
| title_fullStr | 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells |
| title_full_unstemmed | 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells |
| title_short | 1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells |
| title_sort | 1α 25 oh 2d3 reverses exhaustion and enhances antitumor immunity of human cytotoxic t cells |
| url | https://jitc.bmj.com/content/10/3/e003477.full |
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