Innate Immune Activation by Checkpoint Inhibition in Human Patient-Derived Lung Cancer Tissues

Authors

Teresa W. M. Fan, University of KentuckyFollow
Richard M. Higashi, University of KentuckyFollow
Huan Song, University of Kentucky
Saeed Daneshmandi, University of Kentucky
Angela L. Mahan, University of Kentucky
Matthew S. Purdom, University of KentuckyFollow
Therese J. Bocklage, University of KentuckyFollow
Thomas A. Pittman, University of KentuckyFollow
Daheng He, University of KentuckyFollow
Chi Wang, University of KentuckyFollow
Andrew N. Lane, University of KentuckyFollow

Abstract

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with ¹³C₆-Glc/¹³C₅,¹⁵N₂-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1⁺ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.

Document Type

Article

Publication Date

8-18-2021

Notes/Citation Information

Published in eLife, v. 10.

© 2021, Fan et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.7554/elife.69578

Funding Information

University of Louisville (1P01CA163223-01A1): Andrew N Lane; Teresa WM Fan

University of Louisville (1U24DK097215-01A1): Richard M Higashi; Teresa WM Fan; Andrew N Lane

University of Louisville (5P20GM121327): Andrew N Lane

Related Content

All data generated or analysed during this study are included in the manuscript and supporting files. Excel spreadsheets of data used for tables and figures have been deposited at Dryad.

The following data sets were generated:

Lane AN Fan TWM Higashi RM Song H Daneshmandi S Mahan AL Purdom MS Pittman TA He D Wang C (2021) Dryad Digital Repository Innate immune activation by checkpoint inhibition in patient-derived lung cancer tissues. https://doi.org/10.5061/dryad.n5tb2rbwc

Repository Citation

Fan, Teresa W. M.; Higashi, Richard M.; Song, Huan; Daneshmandi, Saeed; Mahan, Angela L.; Purdom, Matthew S.; Bocklage, Therese J.; Pittman, Thomas A.; He, Daheng; Wang, Chi; and Lane, Andrew N., "Innate Immune Activation by Checkpoint Inhibition in Human Patient-Derived Lung Cancer Tissues" (2021). Center for Environmental and Systems Biochemistry Faculty Publications. 11.
https://uknowledge.uky.edu/cesb_facpub/11