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Imaging tumor and T cell responses to metabolic and immune modulation

成像肿瘤和 T 细胞对代谢和免疫调节的反应

基本信息

批准号：
10729012
负责人：
Taha Merghoub
金额：
$ 9.1万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-20 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10729012
关键词：
Imaging tumor cell responses metabolic

项目摘要

PROJECT SUMMARY/ABSTRACT Purpose of the project. This application focuses on the use of imaging to better understand, reverse, and monitor immune suppression and metabolism in murine models of aggressive/metastatic breast cancer. High LDH-A and monocarboxylate transporters 1 and 4 (MCT-1 and MCT-4) have been linked to poor prognosis, and greater metastatic potential. Based on clinical analyses of GEO and MSKCC’s cBio Portal: i) tumors with increased expression of genes involved in lactate metabolism are more aggressive and have poor survival, and ii) there is an inverse correlation between the expression of glycolysis genes and immune-related genes. These data support our hypothesis: that high rates of tumor glycolysis leads to a lactic acid-rich tumor microenvironment (TME) with the exclusion of T cells, resulting in more aggressive tumors with a propensity to form metastases. We further hypothesize that reversal of the T cell exclusion with metabolic inhibitors will render tumors that are resistant to immune modulation with checkpoint blockade (CTLA-4, PD-1) to be responsive to the treatment, due to repopulation of T cells within the tumor microenvironment. Here, we propose to use multimodal imaging to explore the mechanisms by which metabolic and immune modulation therapy reverse the restriction and inactivation of cytotoxic T cells in clinically relevant murine models of aggressive breast cancer. We plan to: 1) characterize in vivo changes in tumor lactate and T cell infiltration during LDH-A and MCT-1/4 inhibition; 2) evaluate the responses to adjuvant and neo-adjuvant single and combination therapy (metabolic inhibition and “checkpoint” blockade in vivo); 3) validate the imaging results by assessing correlations between glycolytic biomarkers and T cell infiltration using ex vivo immunofluorescence (IF), immunohistochemistry (IHC), and fluorescence-assisted cell sorting (FACS); and 4) assess the potential for clinical translation. The translational goal is two-fold: 1) to induce regression in primary and metastatic breast cancer, by increasing tumor penetration and effector function of cytotoxic T cells, and 2) to monitor treatment response by non-invasive imaging. Experimental Strategy. We have established several murine models of aggressive breast cancer in immune competent host animals. In Aim 1, in vitro and in vivo studies will define how tumor-cell metabolism affects T cell function, and identify a “therapeutic window” for optimizing the magnitude and timing of T cell repopulation of aggressive murine breast tumors following LDH and MCT pharmacologic inhibition. In Aim 2, metabolic and immune-PET imaging will monitor how changes in the TME (induced by anti-LDH and anti-MCT treatment) affect T cell infiltration and function. Based on Aim 1 and 2 studies, an “optimized” lactate inhibition treatment strategy (established in Aims 1 and 2) will be combined with immune checkpoint blockade (anti-PD1 and anti- CTLA4) and assessed in Aim 3. Imaging will be used to quantitate tumor lactate, the conversion of hyperpolarized 13C-pyruvate to lactate, glycolysis (reflected in FDG uptake) and the trafficking of CD8+ T cells.

项目总结/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response.

LDH-A 通过 HIF 信号调节肿瘤微环境，并调节免疫反应。

DOI：
10.1371/journal.pone.0203965
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Serganova I;Cohen IJ;Vemuri K;Shindo M;Maeda M;Mane M;Moroz E;Khanin R;Satagopan J;Koutcher JA;Blasberg R
通讯作者：
Blasberg R

Interfering with Helios-induced regulatory T cell stability as a strategy for cancer immunotherapy.

干扰 Helios 诱导的调节性 T 细胞稳定性作为癌症免疫治疗的策略。

DOI：
10.21037/tcr.2016.11.23
发表时间：
2016
期刊：
Translational cancer research
影响因子：
0.9
作者：
Zappasodi,Roberta;Merghoub,Taha
通讯作者：
Merghoub,Taha

LDH-A-Modulation and the Variability of LDH Isoenzyme Profiles in Murine Gliomas: A Link with Metabolic and Growth Responses.

DOI：
10.3390/cancers14092303
发表时间：
2022-05-06
期刊：
CANCERS
影响因子：
5.2
作者：
Shindo, Masahiro;Maeda, Masatomo;Myat, Ko;Mane, Mayuresh M.;Cohen, Ivan J.;Vemuri, Kiranmayi;Albeg, Avi S.;Serganova, Inna;Blasberg, Ronald
通讯作者：
Blasberg, Ronald

Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas.

DOI：
10.3390/cancers14092306
发表时间：
2022-05-06
期刊：
CANCERS
影响因子：
5.2
作者：
Maeda, Masatomo;Ko, Myat;Mane, Mayuresh M.;Cohen, Ivan J.;Shindo, Masahiro;Vemuri, Kiranmayi;Serganova, Inna;Blasberg, Ronald
通讯作者：
Blasberg, Ronald

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.

DOI：
10.1016/j.celrep.2022.111412
发表时间：
2022-09-27
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Drozdz, Marek M.;Doane, Ashley S.;Alkallas, Rached;Desman, Garrett;Bareja, Rohan;Reilly, Michael;Bang, Jakyung;Yusupova, Maftuna;You, Jaewon;Eraslan, Zuhal;Wang, Jenny Z.;Verma, Akanksha;Aguirre, Kelsey;Kane, Elsbeth;Watson, Ian R.;Elemento, Olivier;Piskounova, Elena;Merghoub, Taha;Zippin, Jonathan H.
通讯作者：
Zippin, Jonathan H.