Immune cells play a key role in cancer development, maintenance, invasion and metastases. However, while some specific cellular interactions and functions are relatively well understood, other aspects of immune responses in cancer remain entirely unknown. Several outstanding questions include: a) how do interactions occur in real-time in vivo across different cancers? b) how do cytotoxic and other anti-cancer drugs affect the complex immune network in tumors? and c) can drugs that harness immune function be used in a synergistic fashion to enhance anti-cancer efficacy? Until recently it has been difficult to answer such questions since it has not been possible to visualize immune cells within their natural microenvironment. In this project, we will systematically image key immune cells using real-time imaging technologies, and investigate how different anticancer therapies affect their behavior. We hypothesize that commonly used drugs do indeed affect immune cell behavior, and that they can be chosen and/or combined so as to offer additive synergistic anti-tumor effects.
Our specific aims are as follows: 1) To determine the composition and function of tumor-infiltrated immune cell networks in a mouse model of colon adenocarcinoma. We achieve this by first establishing all the necessary tools for intravital imaging. 2) To determine how anti-cancer drugs modulate immune networks in the mouse model of colon adenocarcinoma. To achieve this, we will investigate commonly used cytotoxic drugs, new and promising molecularly targeted agents, as well as NCI top-listed immune agents. Individual drug effects will be studied first, before subsequently investigating the effects of rationally selected drug combinations. 3) To extend our most promising treatment regimen to orthotopic and transgenic mouse cancer models, which better replicate human disease. Clinical translation will be further facilitated by measuring treatment responses using clinically relevant readouts. Ultimately, our goal is to revise current therapeutic options for cancer. To this end, because the proposed work is focused on evaluating clinically approved agents, our findings will not only have high clinical significance but will also be rapidly translatable. This project will employ innovative approaches to study immune interactions and function in real-time. The combined use of genetically engineered mouse models of human disease together with state-of-the-art microscopic imaging approaches will be facilitated through productive collaborations.

Public Health Relevance

The effects of common anticancer drugs on immune host cell networks are currently poorly understood. Yet, having such knowledge would be invaluable toward advancing current therapeutic strategies. Here, we will exploit multiple innovative approaches not only to image immune responses in cancer, but also to investigate the real-time drug effects of clinically approved agents in order to better optimize anti-cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086355-14
Application #
8566735
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$114,245
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Dubach, J Matthew; Kim, Eunha; Yang, Katherine et al. (2017) Quantitating drug-target engagement in single cells in vitro and in vivo. Nat Chem Biol 13:168-173
Vinegoni, Claudio; Fumene Feruglio, Paolo; Brand, Christian et al. (2017) Measurement of drug-target engagement in live cells by two-photon fluorescence anisotropy imaging. Nat Protoc 12:1472-1497
Iaconelli, Jonathan; Lalonde, Jasmin; Watmuff, Bradley et al. (2017) Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. ACS Chem Biol 12:2139-2148
Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:
Miller, Miles A; Weissleder, Ralph (2017) Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior. Adv Drug Deliv Rev 113:61-86
Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:
Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906
Wu, Juwell W; Turcotte, Raphaƫl; Alt, Clemens et al. (2016) Defining Clonal Color in Fluorescent Multi-Clonal Tracking. Sci Rep 6:24303
Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A et al. (2016) Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation. Bioorg Med Chem Lett 26:1265-1271
Vinegoni, Claudio; Dubach, John M; Feruglio, Paolo Fumene et al. (2016) Two-photon Fluorescence Anisotropy Microscopy for Imaging and Direct Measurement of Intracellular Drug Target Engagement. IEEE J Sel Top Quantum Electron 22:

Showing the most recent 10 out of 316 publications