Innate immune activation by checkpoint inhibition in patient-derived lung cancer tissues

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 (mIF), 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.