Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development

定义交叉引发的抗肿瘤 T 细胞特征来指导免疫疗法的开发

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Immunotherapies such as checkpoint blockade have revolutionized cancer therapy, but responses are seen only in a subset of patients. Though tumor-intrinsic factors such as tumor mutational burden (TMB) or IFNγ “inflamed” signature partially predict sensitivity to checkpoint blockade, these correlations are limited—most patients with “inflamed” tumors or high TMB still fail to respond. A critical step for efficacy of T cell-mediated immunotherapies, including checkpoint blockade, is dendritic cell cross-presentation of tumor antigen (Ag) to CD8+ T cells. Cross- presentation in vivo requires Batf3-expressing type 1 dendritic cells (cDC1), though these DC have additional functions, including secretion of T cell-recruiting chemokines, driving tumor-reactive T cell (TRT) responses. Because patients with cDC1-enriched tumors have improved responses to anti-PD1, we developed an in situ vaccination (ISV) combining FLT3L, radiotherapy (XRT), and TLR agonism to enhance cDC1 cross-priming of TRT and observed that ISV potentiated anti-tumor effects of PD1 blockade and induced systemic tumor regressions in treated patients. Additionally, we have shown that adoptive transfer of tumor-specific T cells into syngeneic RAG-/- mice clears tumors, while transfer into allogeneic RAG-/- mice fails to control tumor growth, highlighting that APC cross-priming of CD8+ T cells is required for efficacy of antitumor T cells. Despite the critical role of cDC1 cross-priming of CD8+ T cells for effective therapy, there is no established method for measuring T cell cross- or direct-priming in vivo. Consequently, there is a critical need for methods to directly measure CD8+ T cell cross-priming for identifying novel therapeutic targets to enhance cross-priming, and to understand mechanisms of therapy resistance. We hypothesize that cross- and direct-primed T cells, and ISV-primed vs untreated T cells, will harbor distinct signatures, mirroring their differential antitumor efficacy. In Aim 1, we will develop mouse models of cross- and direct-priming using H2Kd knockout, H2Kb-transfected, GFP/OVA- expressing lymphoma and breast cancers and transfer of Ag-specific T cells into syngeneic and allogeneic RAG-/- mice. We will sort tumor-reactive T cells and perform bulk RNA-seq and spectral flow cytometry to identify a cross-primed CD8+ T cell signature. In Aim 2, we will use bulk RNA-seq and spectral flow cytometry to characterize the T cell response to ISV and checkpoint blockade across tumors (lymphoma, breast cancer), model antigens (GFP, OVA, luciferase), and endogenous tumor antigens. The outcome of this study will be elucidation of a cross-primed CD8+ T cell phenotype and a novel immune monitoring technique that allows targeted design of novel immunotherapies by targeting novel checkpoints or costimulators to increase cross- priming of tumor-reactive T cells.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gabrielle Lubitz其他文献

Gabrielle Lubitz的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gabrielle Lubitz', 18)}}的其他基金

Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development
定义交叉引发的抗肿瘤 T 细胞特征来指导免疫疗法的开发
  • 批准号:
    10677596
  • 财政年份:
    2022
  • 资助金额:
    $ 4.52万
  • 项目类别:

相似海外基金

Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
  • 批准号:
    10682121
  • 财政年份:
    2023
  • 资助金额:
    $ 4.52万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10576370
  • 财政年份:
    2022
  • 资助金额:
    $ 4.52万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10387023
  • 财政年份:
    2022
  • 资助金额:
    $ 4.52万
  • 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10248409
  • 财政年份:
    2019
  • 资助金额:
    $ 4.52万
  • 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
  • 批准号:
    nhmrc : GNT1163111
  • 财政年份:
    2019
  • 资助金额:
    $ 4.52万
  • 项目类别:
    Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10462684
  • 财政年份:
    2019
  • 资助金额:
    $ 4.52万
  • 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
  • 批准号:
    398018062
  • 财政年份:
    2018
  • 资助金额:
    $ 4.52万
  • 项目类别:
    Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9308643
  • 财政年份:
    2017
  • 资助金额:
    $ 4.52万
  • 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9447149
  • 财政年份:
    2017
  • 资助金额:
    $ 4.52万
  • 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
  • 批准号:
    8893915
  • 财政年份:
    2014
  • 资助金额:
    $ 4.52万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了