Project 2 - Modulation of Anti-Tumor Immunity by Inhibitory Receptors
项目2——抑制性受体调节抗肿瘤免疫
基本信息
- 批准号:10670296
- 负责人:
- 金额:$ 44.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
Cell surface inhibitory receptors (IRs) PD1 and LAG3 control cellular signaling and critical cell intrinsic effector
T cell function and differentiation. Yet, these IRs are also expressed on exhausted intratumoral T cells, limiting
disease clearance. IRs are critical to maintain immune control, but also represent a major barrier to effective
anti-tumor immunity. PD1 and LAG3 are synergistic in multiple diseases, including cancers, and many CD8+ and
CD4+ tumor-infiltrating lymphocytes (TILs) express PD1/LAG3. Indeed, we showed that tumor immunotherapy
targeting PD1/LAG3 can induce almost complete remission of tumors in mice, and clinical evidence now supports
the benefit of single (anti-PD1) or dual (anti-PD1/LAG3) IR blockade. This project will test the central hypothesis
that “PD1 and LAG3 synergize to enforce tumor-induced tolerance using a combination of overlapping and
unique cell intrinsic and extrinsic functions in CD4+ and CD8+ effector T cells”. Due to potency of tolerance in the
tumor microenvironment (TME), mouse models represent an outstanding system to study IR mechanisms to
compare with processes in autoimmune (Project 1) and chronic viral settings (Project 3). We will pursue 3 Aims:
AIM 1: What are the relative and synergistic contributions of PD1 and LAG3 in limiting the initial CD8+ T
cell anti-tumor effector response? We hypothesize that “PD1 and LAG3 do not initiate but temporally reenforce progression toward CD8+ T cell exhaustion by limiting population dynamics, differentiation, metabolic
health, and polyfunctionality”. We will use a Quad AT system that co-transfers tumor-specific CD8+ T cells that
are wild-type or lack PD1 and/or LAG3 for functional and transcriptional analysis in the same microenvironment.
AIM 2: What are the relative and synergistic contributions of PD1 and LAG3 in limiting initial CD4+ Tconv
anti-tumor effector response? We hypothesize that “PD1/LAG3 have synergistic effects on CD4+ Tconv cells
by differentially modulating their function and capacity for CD8+ T cell help”. We will interrogate the role of
PD1/LAG3 on CD4+ T cells using our novel CreERT2 line to delete alleles in CD4+ Tconv but not CD8+ T cells or
Tregs.
AIM 3: What is the impact of PD1/LAG3 on the durability of anti-tumor T cell memory and maintenance
of systemic immunity? We hypothesize that “PD1 and/or LAG3 limit durability of anti-tumor immunity by
impacting Tex reinvigoration and Tconv cell memory development and maintenance, blunting their recall response
and limiting systemic immunity”. We will ask 2 questions: (A) What is the impact of PD1/LAG3 loss on Tex and
their reinvigoration? (B) What is the impact of PD1/LAG3 on maintenance of T cell anti-tumor memory and recall
response?
PPG Interactions: Project 2 will collaborate with Project 1 to compare the impact of PD1/LAG3 loss on CD4+
T cell function in autoimmune versus tumoral settings; with Project 3 to compare CD8+ T cell exhaustion induced
by tumors or chronic viral infections; and with Core A to exchange data, Core B to obtain mice, Core C for
transcriptional analysis and CRISPR/sgRNA sequences, and Core D for immunohistological analysis.
项目总结
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)
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Dario AA Vignali其他文献
The extent of metalloproteinase-mediated LAG3 cleavage limits the efficacy of PD1 blockade
- DOI:
10.1186/2051-1426-3-s2-p216 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Lawrence P Andrews;Andrea L Szymczak-Workman;Creg J Workman;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Remodulation of the tumor microenvironment by regulatory T cells
- DOI:
10.1186/2051-1426-3-s2-p409 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Chang Liu;Maria Chikina;Creg J Workman;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Elucidating the role of Neuropilin-1 in intra-tumoral regulatory T cell stability
- DOI:
10.1186/2051-1426-3-s2-p274 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Abigail E Overacre;Maria Chikina;Greg M Delgoffe;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Antigen presentation by tumor infiltrating B cells influences CD4 T cell phenotype and function in primary lung cancer patient tumors
- DOI:
10.1186/2051-1426-3-s2-p397 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Tullia Bruno;Peggy Ebner;Brandon Moore;Daniel Munson;John Mitchell;Jeffrey Kern;Dario AA Vignali;Jill Slansky - 通讯作者:
Jill Slansky
Dario AA Vignali的其他文献
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{{ truncateString('Dario AA Vignali', 18)}}的其他基金
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10454307 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目1:评估LAG3和PD-1在黑色素瘤患者中的协同作用
- 批准号:
10683756 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目 1:评估 LAG3 和 PD-1 在黑色素瘤患者中的协同作用
- 批准号:
10469635 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10298246 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10670939 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目 1:评估 LAG3 和 PD-1 在黑色素瘤患者中的协同作用
- 批准号:
10270231 - 财政年份:2021
- 资助金额:
$ 44.51万 - 项目类别:
Interleukin-35 and the tumor microenvironment
Interleukin-35 与肿瘤微环境
- 批准号:
9306799 - 财政年份:2016
- 资助金额:
$ 44.51万 - 项目类别:
Synergies among inhibitory receptors in tolerance, cancer & antiviral immunity
抑制性受体在耐受性、癌症方面的协同作用
- 批准号:
10470821 - 财政年份:2015
- 资助金额:
$ 44.51万 - 项目类别:
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