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.

设计了几种当前的肿瘤免疫疗法（例如PD-1/PD-L1阻滞和肿瘤疫苗）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效率并受益 更多的癌症患者，迫切需要提高我们对细胞和分子机制的了解 内源性肿瘤特异性T细胞的反应。重要的是，抗原特异性CD8+ T的子集 细胞已被鉴定为干细胞状或祖细胞样，这是对PD-1/PD-的反应 L1封锁和肿瘤疫苗。但是，我们对这些类似Tem的T细胞对肿瘤的反应一无所知 疫苗。 沿着小鼠急性感染模型的不同研究，组织居住的记忆T细胞（TRM）具有 被确定为独特的记忆T细胞群体。与其他迁移的T细胞子集相反，TRM DO 长时间不重新循环并驻留在特定组织（主要是非淋巴组织）内。我们 其他人则在急性感染后建立TGF-B在建立TRM中发挥了关键作用。我们的 初步发现表明，肿瘤排出淋巴结（TDLN）是独特的储层 托有类似茎状肿瘤特异性CD8+ T细胞。令人惊讶的是，这些TDLN茎样T细胞中很大一部分 以TGF-B依赖性方式采用TRM表型。此外，我们发现野生型TDLN茎 - 像T细胞一样迅速，但在肿瘤疫苗后瞬时失去TRM表型。相反，TGF-B受体默认 TDLN茎状的T细胞在基线时具有显着降低的TRM表型，并且暴露得非常增强，并且 对肿瘤疫苗的长期反应。 TDLN中的增强响应被转化为增加的迁移 从TDLN到肿瘤，以及TGF-B受体缺乏CD8+ T细胞的更好肿瘤控制。重要的是，抑制 T细胞迁移完全废除了TGF-B受体缺乏CD8+ T细胞的肿瘤疫苗的反应。 总之，我们的结果支持一个工作模型，该模型很大一部分茎状T细胞分化为TRM 在TDLN内部，不会迁移到肿瘤部位。茎样T细胞需要丧失组织 - 栖息 分化为迁移效应，并对肿瘤疫苗产生强大的反应。抑制组织居住 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 茎状T细胞的分化和迁移，这将导致响应某些人的肿瘤控制更好 肿瘤免疫疗法。在当前建议中，我们将直接测试针对TGF-B或TRM签名是否将 提高茎状T细胞的迁移，从而提高肿瘤疫苗的效率以及局部 辐照释放内源性肿瘤抗原。 总之，我们的建议主要集中于肿瘤期间茎状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翻译潜力 TGF-B抑制剂和TRM靶向策略是对肿瘤免疫疗法的“普遍调整”。此外， 我们的投资将促进看似不同的研究领域之间的沟通，即TRM，STEM- 像T细胞和肿瘤免疫疗法一样，它将在不久的将来培养新的热干预措施。