The PI's previous work unveiled a novel mechanism of vascularization in human and mouse ovarian carcinoma: beta-defensins were shown to massively recruit CD45+CD11c+CCR6+ myeloid cells to the tumor microenvironment, where they were transformed by VEGF in vivo into endothelial-like cells, termed Vascular Leukocytes (VLCs). VLCs express markers - and have physiologic characteristics - of both endothelial cells and dendritic cell precursors. Our central hypothesis is that VLCs are a specific lineage of CD11c+ myeloid cells that significantly contributes to vascularization during tumor formation;as such, these cells may represent important and novel therapeutic targets in the treatment of cancer. This hypothesis is based on the following observations: First, mouse and human VLCs sorted from tumor specimens can create perfusable blood vessels in vivo under angiogenic conditions. Second, our results show that CD45+CD11c+ cells labelled with GFP accumulate within tumor blood vessels. Third, the depletion of CD11c+ cells in suitable ITGAX-DTR-GFP mouse model resulted in a dramatic decrease in tumor growth. The long-term objectives of our research are to determine the exact origin of VLCs and their involvement in tumor vasculogenesis, in order to design new clinically effective cancer interventions.
In Specific Aim 1, we will determine the origin of leukocytes with vasculogenic potential. Mice will be depleted of VLCs, and then challenged with tumors admixed with different subsets of labelled leukocytes, enabling us to precisely define which leukocyte subset(s) are capable of contributing to vascularization.
Specific Aim 2 will assess the stage in tumor development at which VLCs contribute to tumor vascularization. We propose to generate a transgenic mouse with permanently """"""""tagged"""""""" VLCs, permitting the ready identification of this subset over time, even if they lose their leukocyte phenotype during the process of endothelialization.
Specific Aim 3 will evaluate the effectiveness of VLC depletion as a therapeutic intervention in cancer, focusing on the efficacy of anti-VLC immunotoxins homed to the tumor microenvironment. These endeavours will lead to new insights into the mechanisms of tumor vasculogenesis and provide a basis for a more effective targeting of the ovarian cancer microenvironment, focused on triggering an effective immune response while impeding tumor vascularization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA124515-03S1
Application #
7915930
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Howcroft, Thomas K
Project Start
2009-08-01
Project End
2010-09-15
Budget Start
2009-08-01
Budget End
2010-09-15
Support Year
3
Fiscal Year
2009
Total Cost
$155,391
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Saglam, Ozlen; Conejo-Garcia, Jose (2018) PD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer. Integr Cancer Sci Ther 5:
Perales-Puchalt, Alfredo; Perez-Sanz, Jairo; Payne, Kyle K et al. (2018) Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy. J Leukoc Biol 103:799-805
Perales-Puchalt, Alfredo; Svoronos, Nikolaos; Rutkowski, Melanie R et al. (2017) Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 23:441-453
Conejo-Garcia, Jose R; Payne, Kyle K; Svoronos, Nikolaos (2017) Estrogens drive myeloid-derived suppressor cell accumulation. Oncoscience 4:5-6
Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Allegrezza, Michael J et al. (2017) Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 7:72-85
Stephen, Tom L; Payne, Kyle K; Chaurio, Ricardo A et al. (2017) SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells. Immunity 46:51-64
Bitler, Benjamin G; Wu, Shuai; Park, Pyoung Hwa et al. (2017) ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19:962-973
Yokoyama, Yuhki; Zhu, Hengrui; Lee, Jeong Heon et al. (2016) BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res 76:6320-6330
Zhu, Hengrui; Bengsch, Fee; Svoronos, Nikolaos et al. (2016) BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep 16:2829-2837
Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res 76:6253-6265

Showing the most recent 10 out of 57 publications