Highlights
- •The brain microenvironment, including brain metastases (BM), is “immunologically cold”.
- •The mechanism of action of immunotherapy in the brain or BMs is not well understood.
- •Intracranial responses can occur in patients with NSCLC receiving immunotherapy.
- •Understanding the interplay of microenvironment and BMs may improve immunotherapy outcomes.
Abstract
Background
Brain metastases are frequent complications in patients with non-small-cell lung cancer
(NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give
a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting
and to review the role of biomarkers and molecular interactions in brain metastases
from patients with NSCLC.
Methods
We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with
brain metastases as well as publications assessing the tumor microenvironment and
the complex molecular interactions of tumor cells with immune and resident cells in
brain metastases from NSCLC biopsies or preclinical models.
Results
Although limited data are available on immunotherapy in patients with brain metastases,
immune checkpoint inhibitors alone or in combination with chemotherapy have shown
promising intracranial efficacy and safety results. The underlying mechanism of action
of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment
are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors,
suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes
and tumor associated macrophages are paramount in NSCLC brain metastases and play
a role in promoting tumor progression and immune evasion.
Conclusions
Discordances in the immune profile between primary tumours and brain metastases underscore
differences in the tumour microenvironment and immune system interactions within the
lung and brain niche. The characterization of immune phenotype of brain metastases
and dissecting the interplay among immune cells and resident stromal cells along with
cancer cells is crucial to unravel effective immunotherapeutic approaches in patients
with NSCLC and brain metastases.
Keywords
Abbreviations:
NSCLC (non-small-cell lung cancer), TILs (tumor infiltrating lymphocytes), PD-L1 (programmed death ligand-1), TMB (tumor mutational burden), WBRT (whole brain radiotherapy), BSC (best supportive care), OS (overall survival), iCRR (intracranial response rate), ORR (overall response rate), EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), TKIs (tyrosine kinase inhibitors), CNS (central nervous system), PD-1 (programmed death protein-1), PFS (progression free survival), EAP (expanded access programs), DCR (disease control rate), iDCR (intracranial disease control rate), IHC (immunohistochemistry), RA (reactive astrocytes), cGAMP (cyclic guanosine monophosphate-adenosine monophosphate), ncRNAs (non-coding RNAs), ET-1 (endothelin-1), VEGF-A (vascular endothelial growth factor-A), TIMP-1 (tissue inhibitor of metalloproteinases-1), ECM (extracellular matrix), MIF (migration inhibitory factor), NO (nitric oxide), TGF-β (transforming growth factor-β), MCP-1 (monocyte chemoattractant protein), PGE-2 (prostaglandin E2), TAM (tumor associated macrophages), BMDM (bone marrow-derived macrophages)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: July 06, 2020
Accepted:
June 26,
2020
Received in revised form:
June 1,
2020
Received:
April 12,
2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
