Targeting lymphoid tissue residency to boost tumor immunotherapies

靶向淋巴组织驻留以促进肿瘤免疫治疗

• 批准号: 10481357
• 负责人: Nu Zhang
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481357
• 关键词: Adjuvant; Adopted; Affinity; Antigens; Area; Aryl Hydrocarbon Receptor; Biology; CD8-Positive T-Lymphocytes; Cancer Patient; Cancer Vaccines; Cells; Communication; Defect; Development; Exhibits; Future; Genetic; Genetic Transcription; Harvest; Health; Healthcare Systems; Immune; Immune Targeting; Immune response; Immune system; Immunotherapy; Investigation; Knowledge; Lymph Node Tissue; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Mus; Names; PD-1/PD-L1; PD-L1 blockade; Patients; Pattern; Phenotype; Population; Research; Residencies; Role; Signal Transduction; Site; System; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transforming Growth Factors; Translating; Tumor Antigens; Tumor Immunity; Veterans; acute infection; cancer survival; cancer vaccination; cell motility; design; draining lymph node; drug candidate; experience; experimental study; immune checkpoint blockade; improved; improved outcome; inhibitor; insight; irradiation; migration; neoplasm immunotherapy; novel therapeutic intervention; pathogen; pharmacologic; prevent; progenitor; programs; rational design; receptor; response; stem; stem cell biology; stem cell differentiation; stem cells; stem-like cell; synergism; tissue resident memory T cell; transcription factor; translational potential; tumor

Several current tumor immunotherapies (e.g., PD-1/PD-L1 blockade and tumor vaccine) are designed to boost endogenous tumor-specific T cell responses. To improve the efficacy of current immunotherapies and benefit more cancer patients, it is urgent to advance our knowledge about the cellular and molecular mechanisms underlying the response of endogenous tumor-specific T cells. Importantly, a subset of antigen-specific CD8+ T cells have been identified as stem cell-like or progenitor-like, which are the ones responding to both PD-1/PD- L1 blockade and tumor vaccine. However, we know little about how these stem-like T cells respond to tumor vaccine. Along a different line of research in mouse acute infection models, tissue-resident memory T cells (TRM) have been identified as a unique population of memory T cells. In contrast to other migratory T cell subsets, TRMs do not re-circulate and reside inside a particular tissue (mostly non-lymphoid tissues) for an extended period. We and others have established a critical role for TGF-b in the establishment of TRM after acute infection. Our preliminary findings have demonstrated that tumor draining lymph nodes (TDLNs) function as a unique reservoir to host stem-like tumor-specific CD8+ T cells. Surprisingly, a substantial portion of these TDLN stem-like T cells adopt a TRM phenotype in a TGF-b-dependent manner. Further, we have discovered that wild type TDLN stem- like T cells rapidly, but transiently lose TRM phenotype after tumor vaccine. In contrast, TGF-b receptor deficient TDLN stem-like T cells carry significantly reduced TRM phenotype at baseline and exhibit greatly enhanced and prolonged response to tumor vaccine. The enhanced response in TDLN is translated into increased migration from TDLN to tumor and better tumor control for TGF-b receptor deficient CD8+ T cells. Importantly, inhibition of T cell migration completely abolishes the response to tumor vaccine for TGF-b receptor deficient CD8+ T cells. Together, our results support a working model that a significant portion of stem-like T cells differentiate into TRM inside TDLN and will not migrate to tumor site. Loss of tissue-residency is required for stem-like T cells to differentiate into migratory effectors and elicit robust response to tumor vaccine. Suppression of tissue-residency in TDLN (e.g., deletion of TGF-b receptor or TGF-b downstream molecular targets) will greatly boost the differentiation and migration of stem-like T cells, which will lead to better tumor control in response to certain tumor immunotherapies. In current proposal, we will directly test whether targeting TGF-b or TRM-signature will boost the migration of stem-like T cells and therefore enhance the efficacy of tumor vaccine as well as local irradiation released endogenous tumor antigen. Together, our proposal is primarily focused on the TRM biology of stem-like CD8+ T cells during tumor immunotherapies, with a special emphasis on TDLN. Our results will have great translational potential to use TGF-b inhibitors and TRM-targeting strategies as a “universal adjuvant” for tumor immunotherapies. In addition, our investigation will facilitate the communication between seemly distinct research areas, namely TRM, stem- like T cells and tumor immunotherapies, which will cultivate novel therapeutic interventions in the near future.

当前的几种肿瘤免疫疗法（例如 PD-1/PD-L1 阻断和肿瘤疫苗）旨在增强 内源性肿瘤特异性 T 细胞反应。提高当前免疫疗法的功效和效益 随着癌症患者数量的增加，迫切需要提高我们对细胞和分子机制的认识 内源性肿瘤特异性 T 细胞反应的基础。重要的是，抗原特异性 CD8+ T 的一个子集 细胞已被鉴定为干细胞样或祖细胞样，它们对 PD-1/PD- 都有反应。 L1 阻断和肿瘤疫苗。然而，我们对这些干细胞样 T 细胞如何响应肿瘤知之甚少 疫苗。 沿着小鼠急性感染模型的不同研究方向，组织驻留记忆 T 细胞 (TRM) 被鉴定为独特的记忆 T 细胞群。与其他迁移性 T 细胞亚群相比，TRM 确实 不会再循环并长时间驻留在特定组织（主要是非淋巴组织）内。我们 等人已经确定了 TGF-b 在急性感染后 TRM 建立中的关键作用。我们的 初步研究结果表明，肿瘤引流淋巴结（TDLN）具有独特的储库功能 宿主干细胞样肿瘤特异性 CD8+ T 细胞。令人惊讶的是，这些 TDLN 干样 T 细胞的很大一部分 以 TGF-b 依赖性方式采用 TRM 表型。此外，我们发现野生型 TDLN 干- 快速像T细胞一样，但在肿瘤疫苗接种后短暂失去TRM表型。相反，TGF-b受体缺陷 TDLN 干样 T 细胞在基线时携带显着降低的 TRM 表型，并表现出极大增强和 对肿瘤疫苗的长期反应。 TDLN 中响应的增强转化为迁移的增加 从 TDLN 到肿瘤，并更好地控制 TGF-b 受体缺陷型 CD8+ T 细胞的肿瘤。重要的是，抑制 T 细胞迁移完全消除了 TGF-b 受体缺陷的 CD8+ T 细胞对肿瘤疫苗的反应。 总之，我们的结果支持了一个工作模型，即很大一部分干细胞样 T 细胞分化为 TRM 位于 TDLN 内部，不会迁移至肿瘤部位。干细胞样 T 细胞需要失去组织驻留性 分化为迁移效应细胞并引起对肿瘤疫苗的强烈反应。抑制组织驻留 在 TDLN 中（例如，删除 TGF-b 受体或 TGF-b 下游分子靶标）将大大提高 干细胞样T细胞的分化和迁移，这将导致更好的肿瘤控制以响应某些 肿瘤免疫疗法。在当前的提案中，我们将直接测试靶向 TGF-b 或 TRM-signature 是否会 促进干细胞样T细胞的迁移，从而增强肿瘤疫苗以及局部的功效 辐射释放出内源性肿瘤抗原。 总之，我们的提案主要集中在肿瘤过程中干细胞样 CD8+ T 细胞的 TRM 生物学 免疫疗法，特别强调 TDLN。我们的结果将具有巨大的转化潜力 TGF-b 抑制剂和 TRM 靶向策略作为肿瘤免疫疗法的“通用佐剂”。此外， 我们的调查将促进看似不同的研究领域之间的交流，即TRM、干- 例如 T 细胞和肿瘤免疫疗法，这将在不久的将来培育出新的治疗干预措施。