Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens

系统研究患者来源标本中的胰腺癌微环境

• 批准号: 10250566
• 负责人: William C. Hahn
• 金额: $ 56.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250566
• 关键词: Aftercare; Atlases; Biology; Biopsy; Biopsy Specimen; CC chemokine receptor 2; CD8-Positive T-Lymphocytes; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Coculture Techniques; Combination immunotherapy; Combined Modality Therapy; Complex; Cytotoxic Chemotherapy; Cytotoxic agent; Dana-Farber Cancer Institute; Desmoplastic; Devices; Disease; Elements; Evaluation; Evolution; Excision; FLT3 ligand; Fibroblasts; Future; Genetic; Genetically Engineered Mouse; Genomics; Heterogeneity; Human; Immune; Immune response; Immunocompetent; Immunofluorescence Immunologic; Immunologist; Immunosuppression; Immunotherapy; Interferon Type II; Interleukin-15; KRASG12D; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Microfluidic Microchips; Microfluidics; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Neoadjuvant Therapy; Non-Malignant; Oncologist; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Periodicity; Phase Ib/II Clinical Trial; Phenotype; Play; Pre-Clinical Model; Prognosis; Proteomics; Radiation; Radiation therapy; Randomized; Regimen; Renal Cell Carcinoma; Research; Resectable; Resolution; Role; Sampling; Specimen; Survival Rate; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Tumor-infiltrating immune cells; cancer type; cell type; checkpoint inhibition; chemotherapy; cytokine; early phase clinical trial; effective therapy; gemcitabine; immune checkpoint blockade; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; improved; inhibitor/antagonist; macrophage; melanoma; mouse model; multidisciplinary; neoplastic cell; novel; novel strategies; pancreatic cancer patients; pre-clinical; prevent; programs; recruit; response; single-cell RNA sequencing; spatial relationship; success; targeted delivery; targeted treatment; therapeutic evaluation; transcriptome; transcriptome sequencing; transcriptomics; treatment research; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of only 8%. Despite success in other cancer types, immunotherapy approaches in PDAC have not shown efficacy. PDAC demonstrates a heterogeneous and immunosuppressive tumor microenvironment (TME) that is poorly understood and serves as a barrier to effective immunotherapy strategies in this disease. We propose that an improved understanding of the TME and novel approaches that target key tumor-stroma interactions will enable remodeling of the immunosuppressive TME to enhance the efficacy of current and future immunotherapy strategies. In particular, we believe that successful combination immunotherapy approaches in PDAC will include strategies that alter myeloid cells to relieve immunosuppression, cytotoxic therapies that target tumor cells to improve immune response, and agents that augment anti-tumor T cell activity. In this project, we will perform a comprehensive characterization of the PDAC TME in both primary and metastatic PDAC in the baseline untreated context as well as across multiple different clinical therapies. In Aim 1, we will utilize single-cell transcriptomic and proteomic technologies to provide a cellular atlas of the PDAC TME at unprecedented resolution. In Aim 2, we will examine how the PDAC TME changes with chemotherapy, radiation therapy and a novel CCR2 inhibitor that modulates macrophage recruitment in the TME. For these studies, we will utilize human samples derived from both resectable and metastatic patients on clinical trials at Dana-Farber Cancer Institute. We will employ a novel ex vivo co-culture approach to enable rapid functional evaluation of tumor-stroma interactions and how they may impact immunotherapy responses. Lastly, in Aim 3 we will employ faithful immune competent PDAC mouse models and a novel cytokine delivery platform to investigate how targeted cytokine delivery to the TME may alter myeloid cell recruitment and function and improve immune responses. We have assembled a multi-disciplinary collaborative team including experts in PDAC biology and genetics, immunologists and translational oncologists to comprehensively study PDAC TME and identify novel opportunities to develop combination immunotherapy approaches in this devastating disease.

抽象的 胰腺导管腺癌（PDAC）是一种致命疾病，其存活率仅为8％。尽管 在其他癌症类型的成功中，PDAC中的免疫疗法方法尚未显示出功效。 PDAC 表现出异质和免疫抑制性肿瘤微环境（TME） 理解并成为该疾病有效免疫疗法策略的障碍。我们建议 对针对关键肿瘤相互作用的TME和新颖方法的了解得以提高 启用对免疫抑制性TME的重塑以增强当前和未来的功效 免疫疗法策略。特别是，我们认为成功的组合免疫疗法方法 PDAC将包括改变髓样细胞以减轻免疫抑制，细胞毒性疗法的策略 靶向肿瘤细胞以改善免疫反应，并增强抗肿瘤T细胞活性的药物。在这个 项目，我们将对主要和转移的PDAC TME进行全面表征 基线未经处理的环境以及多种不同临床疗法的PDAC。在AIM 1中，我们将 利用单细胞转录组和蛋白质组学技术提供PDAC TME的细胞图集 空前的解决方案。在AIM 2中，我们将研究PDAC TME如何随化学疗法而变化， 放射疗法和一种新型的CCR2抑制剂，可调节TME中的巨噬细胞募集。为此 研究，我们将利用源自可切除和转移性患者的人类样本 达纳 - 法伯癌研究所。我们将采用一种新型的离体共文化方法来启用快速功能 评估肿瘤性肿瘤相互作用及其如何影响免疫疗法反应。最后，在AIM 3中 我们将采用忠实的免疫能力的PDAC鼠标模型和新型的细胞因子输送平台 研究靶向细胞因子向TME递送如何改变髓样细胞的募集和功能，以及 改善免疫反应。我们组建了一个多学科的合作团队，包括 PDAC生物学和遗传学，免疫学家和转化肿瘤学家全面研究PDAC TME 并确定在这种毁灭性的情况下开发组合免疫疗法方法的新型机会 疾病。

项目成果

Pan-cancer Transcriptomic Predictors of Perineural Invasion Improve Occult Histopathologic Detection.

• DOI: 10.1158/1078-0432.ccr-20-4382
• 发表时间: 2021-05-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Guo JA;Hoffman HI;Shroff SG;Chen P;Hwang PG;Kim DY;Kim DW;Cheng SW;Zhao D;Mahal BA;Alshalalfa M;Niemierko A;Wo JY;Loeffler JS;Fernandez-Del Castillo C;Jacks T;Aguirre AJ;Hong TS;Mino-Kenudson M;Hwang WL
• 通讯作者: Hwang WL

Radiation and Local Anti-CD40 Generate an Effective in situ Vaccine in Preclinical Models of Pancreatic Cancer.

• DOI: 10.3389/fimmu.2018.02030
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Yasmin-Karim S;Bruck PT;Moreau M;Kunjachan S;Chen GZ;Kumar R;Grabow S;Dougan SK;Ngwa W
• 通讯作者: Ngwa W

Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer.

• DOI: 10.1098/rsob.210245
• 发表时间: 2021-11
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Stump CT;Roehle K;Manjarrez Orduno N;Dougan SK
• 通讯作者: Dougan SK

Cancer Immunotherapy: Beyond Checkpoint Blockade.

• DOI: 10.1146/annurev-cancerbio-030518-055552
• 发表时间: 2019-03
• 期刊: ANNUAL REVIEW OF CANCER BIOLOGY
• 影响因子: 7.7
• 作者: Dougan, Michael;Dranoff, Glenn;Dougan, Stephanie K.
• 通讯作者: Dougan, Stephanie K.