Journal Article

Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging

Engblom, Camilla, Dubach, J. Matthew, Miller, Miles A., Cuccarese, Michael F., Weissleder, Ralph, Pfirschke, Christina, Pittet, Mikael J., Garris, Christopher

2017

Overview

Involvement of the immune system in tumour progression is at the forefront of cancer research. Analysis of the tumour immune microenvironment has yielded a wealth of information on tumour biology, and alterations in some immune subtypes, such as tumour-associated macrophages (TAM), can be strong prognostic indicators. Here, we use optical tissue clearing and a TAM-targeting injectable fluorescent nanoparticle (NP) to examine three-dimensional TAM composition, tumour-to-tumour heterogeneity, response to colony-stimulating factor 1 receptor (CSF-1R) blockade and nanoparticle-based drug delivery in murine pulmonary carcinoma. The method allows for rapid tumour volume assessment and spatial information on TAM infiltration at the cellular level in entire lungs. This method reveals that TAM density was heterogeneous across tumours in the same animal, overall TAM density is different among separate pulmonary tumour models, nanotherapeutic drug delivery correlated with TAM heterogeneity, and successful response to CSF-1R blockade is characterized by enhanced TAM penetration throughout and within tumours. Tumour-associated macrophages (TAM) can be used as prognostic indicators in cancer. Here, the authors establish a platform for high-throughput 3D microscopy in murine lung carcinoma that allows to visualize TAMs infiltration throughout the entire lung, response to CSF-1R blockade and nanoparticle drug delivery.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/34 / 631/67/1059/602 / 631/67/1612 / 631/67/2321 / 631/67/327 / 631/67/580 / 64/60 / Aminopyridines - pharmacology / Aminopyridines - therapeutic use / Animals / Antibodies / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biology / Cancer / Carcinoma, Lewis Lung - diagnostic imaging / Carcinoma, Lewis Lung - drug therapy / Carcinoma, Lewis Lung - immunology / Carcinoma, Lewis Lung - pathology / Cell Line, Tumor / Female / Heterogeneity / Humanities and Social Sciences / Humans / Imaging, Three-Dimensional - methods / Immune system / Infiltration / Kinases / Labeling / Lung - diagnostic imaging / Lung - pathology / Lung Neoplasms - diagnostic imaging / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Macrophage Colony-Stimulating Factor - immunology / Macrophage Colony-Stimulating Factor - metabolism / Macrophages - drug effects / Macrophages - immunology / Metastasis / Mice / Mice, Inbred C57BL / Microscopy / Microscopy, Confocal - methods / Microscopy, Fluorescence - methods / multidisciplinary / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - chemistry / Neurosciences / Perfusion - methods / Pyrroles - pharmacology / Pyrroles - therapeutic use / RAW 264.7 Cells / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - immunology / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Tomography, X-Ray Computed / Treatment Outcome / Tumor Burden - drug effects / Tumor Burden - immunology / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / Xenograft Model Antitumor Assays