工程化益生菌用于肿瘤靶向联合化学免疫治疗
Engineered probiotics for tumor-targeted combination chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
新抗原特异性干细胞样记忆 CD4(+) T 细胞介导 CD8(+) T 细胞依赖性免疫治疗 MHC II 类阴性实体瘤
英文原题：Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors.
查看英文原题
Neoantigen-specific stem cell memory-like CD4(+) T cells mediate CD8(+) T cell-dependent immunotherapy of MHC class II-negative solid tumors.
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中文摘要
CD4+ T 细胞在一系列免疫应答中发挥关键作用，既可作为直接效应细胞，也可通过辅助细胞发挥作用，包括对 CD8+ T 淋巴细胞的辅助。在肿瘤中，能够直接识别肿瘤的新抗原（NeoAg）特异性 CD8+ T 细胞已被广泛研究，而 NeoAg 特异性 CD4+ T 细胞的作用则了解较少。
我们在单 T 细胞受体（TCR）克隆型水平以及过继免疫治疗背景下，表征了针对由 MHC-II 缺陷型鳞状细胞癌肿瘤模型（SCC VII）表达的一种经验证 NeoAg（CLTC H129>Q）的小鼠 CD4+ T 细胞应答。
我们发现，天然的 CLTC H129>Q 特异性 repertoire 具有多样性，并包含通过四聚体结合试验和 CD4 依赖性测定的具有不同亲和力的 TCR。尽管存在这些差异，表达高亲和力或中等亲和力 TCR 的 CD4+ T 细胞对来自生长肿瘤的交叉呈递抗原表现出相当的体内增殖，并驱动相似水平的治疗性免疫，而这种免疫依赖于 CD8+ T 细胞和 CD40L 信号传导。使用 NeoAg 特异性 CD4+ T 细胞的过继细胞治疗（ACT）在 TCR 工程化细胞于体外用 IL-7 和 IL-15 而非 IL-2 分化时最为有效，这与扩增增加以及在肿瘤引流淋巴结（tdLNs）中获得并稳定维持 T 干细胞记忆（T SCM）样表型相关。使用 T SCM 样 CD4+ T 细胞进行 ACT 可导致肿瘤微环境中 CD8+ T 细胞的 PD-1 表达降低，并使 tdLNs 中 PD-1+ CD8+ T 细胞的频率增加。这些发现阐明了 NeoAg 特异性 CD4+ T 细胞通过向 CD8+ T 细胞提供辅助来介导抗肿瘤免疫的作用，并突出了其在 ACT 中的治疗潜力。
展开英文摘要原文
CD4 + T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8 + T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8 + T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4 + T cells is less well understood.
We have characterized the murine CD4 + T cell response against a validated NeoAg (CLTC H129>Q ) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy.
We find that the natural CLTC H129>Q -specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4 + T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8 + T cells and CD40L signaling.
Adoptive cellular therapy (ACT) with NeoAg-specific CD4 + T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (T SCM )-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with T SCM -like CD4 + T cells results in lower PD-1 expression by CD8 + T cells in the tumor microenvironment and an increased frequency of PD-1 + CD8 + T cells in tdLNs.
These findings illuminate the role of NeoAg-specific CD4 + T cells in mediating antitumor immunity via providing help to CD8 + T cells and highlight their therapeutic potential in ACT.
论文信息
- 作者
- Brightman SE、Becker A、Thota RR、Naradikian MS、Chihab L、Zavala KS、Ramamoorthy Premlal AL、Griswold RQ
- 第一作者单位
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA, USA.United States
- 通讯作者单位
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA, USA. sps@lji.org.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Nature immunology2023 Aug
- 原文标识
- PubMed 37400675 · DOI 10.1038/s41590-023-01543-9
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