Project II. The tumor ecosystem in cancer progression and immunotherapeutic response PROJECT SUMMARY The goal of this project is to identify the ecological interactions between cancer and immune cells that govern cancer dynamics and response to therapy. We start from the idea that a tumor can be considered an ecosystem or organ, where multiple accessory cell types are interconnected and communicate with each other and with tumor cells, which serve as their clients. Through systems analysis and modeling of functional interactions in the tumor ecosystem on different scales including cellular, protein, and gene expression dynamics at a population and single cell levels this proposal will seek to identify key cellular and molecular regulatory elements in the tumor microenvironment and potential means of their manipulation for therapeutic benefit. We will explore features of, and relationships between, multiple accessory cell types and tumor cells, in experimental models of skin and lung cancer in mice and in human cancer patients (Aim 1). The accessory cells include myeloid cells, dendritic cells, innate lymphoid cells (ILC), neutrophils, eosinophils, endothelial cells, fibroblasts, and regulatory T (Treg) cells. We will also investigate features of mediators of anti-tumor immunity including NK cells, CD4 and CD8 T cells and their specialized subsets. We will use perturbation of the tumor ecology impacting its progression in mice and human patients by established and novel immunotherapeutic modalities including PD1 and CTLA4 blockade and Treg cell depletion. The impact of these perturbations will be assessed through comprehensive analysis of cellular dynamics and states in relation to biological and clinical outcomes to generate predictive models from the data (Aim 2). We will then validate key interaction components in the tumor ecosystem by modeling cell-cell interactions in vitro using tissue mimetic systems and in silico using agent-based models (Aim 3). 1

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA209975-04
Application #
9743105
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Azizi, Elham; Carr, Ambrose J; Plitas, George et al. (2018) Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell 174:1293-1308.e36
Hsin, Jing-Ping; Lu, Yuheng; Loeb, Gabriel B et al. (2018) The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types. Nat Immunol 19:1137-1145
Philip, Mary; Fairchild, Lauren; Sun, Liping et al. (2017) Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545:452-456
Green, Jesse A; Arpaia, Nicholas; Schizas, Michail et al. (2017) A nonimmune function of T cells in promoting lung tumor progression. J Exp Med 214:3565-3575
Carmona-Fontaine, Carlos; Deforet, Maxime; Akkari, Leila et al. (2017) Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci U S A 114:2934-2939
Plitas, George; Konopacki, Catherine; Wu, Kenmin et al. (2016) Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity 45:1122-1134