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.
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.
|Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906|
|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|
|Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:|
|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|
|Pucci, Ferdinando; Garris, Christopher; Lai, Charles P et al. (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-6|
|Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54|
|Roy, Jeremy; Kim, Bongki; Hill, Eric et al. (2016) Tyrosine kinase-mediated axial motility of basal cells revealed by intravital imaging. Nat Commun 7:10666|
|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|
|Wu, Juwell W; Turcotte, Raphaël; Alt, Clemens et al. (2016) Defining Clonal Color in Fluorescent Multi-Clonal Tracking. Sci Rep 6:24303|
Showing the most recent 10 out of 314 publications