Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues.
IF: 8.713
Cited by: 3


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.


cancer biology
human macrophage metabolism
non small cell lung cancer
stable isotope resolved metabolomics
tumor microenvironment

MeSH terms

Antibodies, Monoclonal, Humanized
CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung
Immune Checkpoint Inhibitors
Immunity, Innate
Lung Neoplasms
Neoplasm Metastasis
Programmed Cell Death 1 Receptor
Tumor Microenvironment


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

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