Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response

Merrill, Joseph R.; Inguscio, Alessandra; Chung, Taemoon; Demestichas, Breanna; Garcia, Libia; Habel, Jill; Lewis, David Y.; Janowitz, Tobias; Lyons, Scott K.

Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response

Authors:

Joseph R. Merrill^1,#, Alessandra Inguscio^1,#, Taemoon Chung¹, Breanna Demestichas¹, Libia A. Garcia¹, Jill Habel¹, David Y. Lewis², Tobias Janowitz^1,* and Scott K. Lyons^1,*

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Affiliations:

¹Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724.
²Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
^#These authors contributed equally to this work.

Keywords:

immunotherapy, cancer, imaging, SPECT, luciferase, sodium iodine symporter, metastases, reporter transgene.

Abbreviatons:

mNIS – murine sodium iodide symporter,

SPECT – single photon emission computed tomography,

FRT – flippase recognition target,

GFP – green fluorescent protein,

PGK – phosphoglycerate kinase 1,

EF-1 – elongation factor-1,

PDAC – pancreatic ductal adenocarcinoma,

anti-PD-1 – anti-programmed death receptor 1,

FACS – fluorescence-activated cell sorting,

MIP – maximum intensity projection,

RECIST – Response Evaluation Criteria in Solid Tumors.

Corresponding Author(s):

Scott K. Lyons, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724; slyons@cshl.edu Tobias Janowitz, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724; janowitz@cshl.edu

Conflict of interest statement:

All authors declare that they have no conflicts of interest.

Please cite this article as:

Joseph R. Merrill, Alessandra Inguscio, Taemoon Chung, Breanna Demestichas, Libia Garcia, Jill Habel, David Y. Lewis, Tobias Janowitz and Scott K. Lyons (2023). Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response. Cell Stress 7(8): 59-68. doi: 10.15698/cst2023.08.288

© 2023 Merrill et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Non-invasive imaging of tumors expressing reporter transgenes is a popular preclinical method for studying tumor development and response to therapy in vivo due to its ability to distinguish signal from tumors over background noise. However, the utilized transgenes, such as firefly luciferase, are immu-nogenic and, therefore, impact results when expressed in immune-competent hosts. This represents an important limitation, given that cancer immunology and immunotherapy are currently among the most impactful areas of research and therapeutic development.
Here we present a non-immunogenic preclinical tumor imaging approach. Based on the expression of murine sodium iodide symporter (mNIS), it facilitates sensitive, non-invasive detection of syngeneic tumor cells in immune-competent tumor models without additional immunogenicity arising from exogenous transgenic protein or selection marker expression. NIS-expressing tumor cells internalize the gamma-emitting [^99mTc]pertechnetate ion and so can be detected by SPECT (single photon emission computed tomography). Using a mouse model of pancreatic ductal adenocarcinoma hepatic metastases in immune-competent C57BL/6 mice, we demonstrate that the technique enables the detection of very early metastatic lesions and longitudinal assessment of immunotherapy responses using precise and quantifiable whole-body SPECT/CT imaging.