論文 - 詳細
| RRC ID | 18085 |
|---|---|
| 著者 | Ding ZC, Huang L, Blazar BR, Yagita H, Mellor AL, Munn DH, Zhou G. |
| タイトル | Polyfunctional CD4⁺ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. |
| ジャーナル | Blood |
| Abstract |
The finding that many chemotherapeutic agents have immunostimulatory effects has provided the impetus to combine chemotherapy and immunotherapy for synergistic antitumor effects. However, the critical determinants of effective antitumor immunity after chemotherapy have not been defined. Here we report that adoptive transfer of tumor-specific CD4⁺ T cells after chemotherapy with cyclophosphamide gave rise to polyfunctional CD4⁺ effector cells, which in turn intensified the inflammatory milieu and enhanced the activation of CD8⁺ T cells in the tumor microenvironment. Although this combined chemoimmunotherapy initially resulted in progressive regression of advanced B-cell lymphoma, its therapeutic efficacy was not durable and most mice succumbed to late relapse. Notably, relapse was associated with acquisition of a tolerized phenotype in tumor-specific CD4⁺ T cells, characterized by overexpression of program death-1 (PD-1). Remarkably, effective antitumor immunity was maintained and cure became prevalent when polyfunctional CD4⁺ effector cells were prevented from undergoing PD-1-mediated tolerization, either by antibody blockade of the PD-1-PD-L1 pathway, or targeted ablation of PD-1 in tumor-specific CD4⁺ T cells. Our study suggests that tumor-reactive CD4⁺ T cells act as the "gatekeepers" of the host antitumor immunity in the postchemotherapy setting, thereby their functional status governs the choice between eradication versus regrowth of residual tumors. |
| 巻・号 | 120(11) |
| ページ | 2229-39 |
| 公開日 | 2012-9-13 |
| DOI | 10.1182/blood-2011-12-398321 |
| PII | S0006-4971(20)46404-3 |
| PMID | 22859605 |
| PMC | PMC3447781 |
| MeSH | Animals Antibodies, Blocking Antineoplastic Agents / therapeutic use CD4 Antigens / metabolism Cell Line, Tumor Combined Modality Therapy Cyclophosphamide / therapeutic use Cytotoxicity, Immunologic Female Immunotherapy, Adoptive* Lymphoma, B-Cell / drug therapy Lymphoma, B-Cell / immunology* Lymphoma, B-Cell / prevention & control Lymphoma, B-Cell / therapy* Mice Mice, Inbred BALB C Mice, Knockout Mice, Transgenic Neoplasm Transplantation Programmed Cell Death 1 Receptor / antagonists & inhibitors Programmed Cell Death 1 Receptor / genetics Programmed Cell Death 1 Receptor / metabolism Secondary Prevention T-Lymphocytes, Helper-Inducer / immunology* T-Lymphocytes, Helper-Inducer / metabolism T-Lymphocytes, Helper-Inducer / transplantation* Up-Regulation |
| IF | 17.794 |
| 引用数 | 43 |
| WOS 分野 | HEMATOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| 実験動物マウス | RBRC00904 |