Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids

Document Type

Article

Publication Date

2-1-2018

Abstract

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine-and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/ IKKe inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo. Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens. Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profi ling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts.

Identifier

85041418590 (Scopus)

Publication Title

Cancer Discovery

External Full Text Location

https://doi.org/10.1158/2159-8290.CD-17-0833

e-ISSN

21598290

ISSN

21598274

PubMed ID

29101162

First Page

196

Last Page

215

Issue

2

Volume

8

Grant

CA010815

Fund Ref

National Science Foundation

This document is currently not available here.

Share

COinS