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Reprogramming the Tumor Microenvironment in Pancreas Cancer to Enhance Immunotherapy

重新编程胰腺癌的肿瘤微环境以增强免疫治疗

基本信息

批准号：
10328894
负责人：
NIPUN B. MERCHANT
金额：
$ 37.61万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328894
关键词：
3-Dimensional Address Aftercare Antitumor Response Blood CD8-Positive T-Lymphocytes CTLA4 gene Cancer Remission Cells Characteristics Chemoresistance Clinical Desmoplastic Drug Delivery Systems Feedback Fibroblasts Fibrosis Flow Cytometry Frequencies Genetically Engineered Mouse Growth Growth Factor Immune Immune Tolerance Immune checkpoint inhibitor Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Intervention KRAS2 gene KRASG12D Lead MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mutation Myeloid-derived suppressor cells Oncogenes Oncogenic Outcome PD-1/PD-L1 Patients Phenotype Prediction of Response to Therapy RAS inhibition Regulatory T-Lymphocyte STAT3 gene Safety Signal Transduction Stromal Cells Stromal Neoplasm T-Lymphocyte Therapeutic Treatment Efficacy Tumor Burden Tumor Immunity Tumor-infiltrating immune cells Work anti-CTLA4 antibodies anti-PD-1 anti-tumor immune response cell growth cell type checkpoint inhibition chemokine circulating biomarkers clinical investigation cytokine cytotoxic CD8 T cells design effector T cell immune checkpoint blockade improved in vivo insight knock-down neoplastic cell novel pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model potential biomarker programmed cell death protein 1 response biomarker targeted treatment therapy resistant treatment group treatment response treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Three major contributors to therapeutic resistance that have been difficult to overcome in pancreatic cancer (PDAC) are mutations in the KRAS oncogene, the presence of a dense desmoplastic stroma that acts as a barrier to drug delivery and effector immune cell infiltration, and the immunosuppressive tumor microenvironment (TME) that renders the tumor ineffective to immunotherapy. Our efforts at targeting downstream effectors of oncogenic RAS, have shown that MEK inhibition (MEKi) results in reciprocal activation of STAT3 signaling, which confers therapeutic resistance and continued PDAC cell growth. Combined inhibition of JAK/STAT3 (STAT3i) and MEKi overcomes therapeutic resistance following RAS inhibition that is mediated through parallel feedback loop activation. We have now identified a novel mechanism showing that combined MEKi and STAT3i also inhibits tumor fibrosis and enhances CD8+ cytotoxic T cell (CTL) infiltration to the tumor while downregulating immunosuppressive regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the TME, resulting in reduced tumor burden and improved survival in genetically engineered mouse models (GEMs) of PDAC. In addition, we show that the tumor suppressive effects of MEKi and STAT3i are T cell dependent. This change in the TME, however, is accompanied by sustained PD-L1/PD-1 and CTLA-4 expression. Our preliminary results further show that combined MEKi and STAT3i with PD-1 inhibition can harness the effects of immune checkpoint inhibitors for an enhanced anti-tumor response. Therapeutic strategies that reprogram the tumor stroma to activate T-cell anti-tumor immunity and reverse immune tolerance are of paramount importance as they have the potential to revolutionize treatment for pancreatic cancer and improve clinical outcomes. Our central hypothesis is that MEKi and STAT3i will reprogram cellular components of the PDAC TME to stimulate infiltration of CD8+ CTLs and overcome the immunosuppressive milieu of PDAC to enhance the effects of checkpoint inhibition (CPI) for a durable and sustained anti-tumor response. This will be proven by the following specific aims: Aim 1: Determine if checkpoint inhibition with MEKi and STAT3i will improve survival in GEMs of PDAC. Safety and efficacy of MEKi/STAT3i and anti-PD1 and/or anti-CTLA-4 antibodies treatment response will be determined in two different GEMs of PDAC. Aim 2: Determine if changes in the stromal and immune microenvironment induced by MEKi/STAT3i and checkpoint inhibition result in a durable and sustained anti-tumor immune response in PDAC in vivo. In this aim, multiplex flow cytometry will be used to detect the changes in the cell types and activation phenotypes to determine if the differences pre- and post-treatment predict response. Aim 3: Determine the effects of PDAC cell specific and CAFs specific knockdown of MEK and/or STAT3 signaling on changes in the stromal and immune microenvironment in PDAC. This aim will elucidate the mechanism of cell-specific knockdown of MEK and/or STAT3 mediated changes in that result in increased infiltration CD8+ T cells and suppression of suppressive MDSCs and Tregs. This work will not only evaluate a novel treatment strategy for PDAC, but may uncover potential biomarkers of response to checkpoint inhibitors.

项目总结/文摘

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stroma secreted IL6 selects for "stem-like" population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways.

DOI：
10.1038/s41419-020-03168-4
发表时间：
2020-11-11
期刊：
Cell death & disease
影响因子：
9
作者：
Kesh K;Garrido VT;Dosch A;Durden B;Gupta VK;Sharma NS;Lyle M;Nagathihalli N;Merchant N;Saluja A;Banerjee S
通讯作者：
Banerjee S

Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy.

DOI：
10.1586/epr.10.70
发表时间：
2010-08
期刊：
Expert review of proteomics
影响因子：
3.4
作者：
Nagaraj NS;Singh OV;Merchant NB
通讯作者：
Merchant NB

Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.

DOI：
10.1158/0008-5472.can-13-2329
发表时间：
2014-04-01
期刊：
Cancer research
影响因子：
11.2
作者：
Nagathihalli NS;Beesetty Y;Lee W;Washington MK;Chen X;Lockhart AC;Merchant NB
通讯作者：
Merchant NB

Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma.

MEK和CDK4/6途径的结合封锁可诱导衰老以改善胰腺导管腺癌的生存。

DOI：
10.1158/1535-7163.mct-19-1043
发表时间：
2021-07
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Willobee BA;Gaidarski AA;Dosch AR;Castellanos JA;Dai X;Mehra S;Messaggio F;Srinivasan S;VanSaun MN;Nagathihalli NS;Merchant NB
通讯作者：
Merchant NB

Intensity of follow-up after pancreatic cancer resection.