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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References
- The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.Cancer Treat Rev. 2016; 45: 139-162https://doi.org/10.1016/j.ctrv.2016.03.009
- Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.J Clin Oncol. 2004; 22: 2865-2872https://doi.org/10.1200/JCO.2004.12.149
- Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).Neuro Oncol. 2017; 19: 162-174https://doi.org/10.1093/neuonc/now241
- Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.Lancet Oncol. 2009; 10: 1037-1044https://doi.org/10.1016/s1470-2045(09)70263-3
- Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07–01).Ann Oncol. 2011; 22: 2466-2470https://doi.org/10.1093/annonc/mdr003
- Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).Lancet. 2016; 387: 1415-1426https://doi.org/10.1016/S0140-6736(16)00004-0
- Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.Clin Cancer Res. 2016; 22: 5130-5140https://doi.org/10.1158/1078-0432.CCR-16-0399
- Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.Cancer Chemother Pharmacol. 2014; 74: 1023-1028https://doi.org/10.1007/s00280-014-2578-6
- Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer.N Engl J Med. 2018; 379: 2027-2039https://doi.org/10.1056/NEJMoa1810171
- Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study.Ann Oncol. 2018; 29: 2214-2222https://doi.org/10.1093/annonc/mdy405
- CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study.Ann Oncol. 2017; 28: x196https://doi.org/10.1093/annonc/mdx782
- CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3)..JCO. 2017; 35 (9005–9005)https://doi.org/10.1200/JCO.2017.35.15_suppl.9005
- Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639https://doi.org/10.1056/NEJMoa1507643
- Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135https://doi.org/10.1056/NEJMoa1504627
- Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.Lancet. 2017; 389: 255-265https://doi.org/10.1016/S0140-6736(16)32517-X
Bristol-Myers Squibb Company, Opdivo (nivolumab) prescribing information (US FDA). https://packageinserts.bms.com/pi/pi_opdivo.pdf 2020.
Genentech Inc, Tecentriq (atezolizumab) prescribing information (US FDA). https://www.gene.com/download/pdf/tecentriq_prescribing.pdf 2020.
Merck & Co INC, Keytruda (pembrolizumab) prescribing information (US FDA). https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 2020.
- Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.N Engl J Med. 2016; 375: 1823-1833https://doi.org/10.1056/NEJMoa1606774
- Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.N Engl J Med. 2018; 378: 2078-2092https://doi.org/10.1056/NEJMoa1801005
- Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.N Engl J Med. 2018; 379: 2040-2051https://doi.org/10.1056/NEJMoa1810865
- Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.N Engl J Med. 2018; 378: 2288-2301https://doi.org/10.1056/NEJMoa1716948
- Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350https://doi.org/10.1056/NEJMoa1809697
- Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer.J Thorac Dis. 2018; 10: S1032-S1036
AstraZeneca Pharmaceuticals LP, Imfinzi (durvalumab) prescribing information (US FDA). https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1 2020.
- Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment.Cancer Treat Rev. 2018; 68: 69-79https://doi.org/10.1016/j.ctrv.2018.05.015
- Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer.Ann Oncol. 2016; 27: 1953-1958https://doi.org/10.1093/annonc/mdw289
- Serpins promote cancer cell survival and vascular co-option in brain metastasis.Cell. 2014; 156: 1002-1016https://doi.org/10.1016/j.cell.2014.01.040
- Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 976-983https://doi.org/10.1016/S1470-2045(16)30053-5
- Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.Lancet Oncol. 2020; 21: 655-663https://doi.org/10.1016/S1470-2045(20)30111-X
Goldman JW, Crino L, Vokes EE, Holgado E, Reckamp K, Pluzanski A, et al., Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets). J Thorac Oncol 2016;11:S238–S9. abstr P2.36. https://doi.org/10.1016/j.jtho.2016.08.107.
Molinier O, Audigier-Valette C, Cadranel J, Monnet I, Hureaux J, Hilgers W, et al., IFCT-1502 CLINIVO: Real-Life Experience with Nivolumab in 600 Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol 2017;12:S1793. abstr OA 17.05. https://doi.org/10.1016/j.jtho.2017.09.430.
- Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.Lung Cancer. 2019; 129: 35-40https://doi.org/10.1016/j.lungcan.2018.12.025
- Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042.Ann Oncol. 2019; 30: v604-v606https://doi.org/10.1093/annonc/mdz260.004
- Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407.Ann Oncol. 2019; 30: v606-v607https://doi.org/10.1093/annonc/mdz260.005
- Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.J Thorac Oncol. 2019; 14: 1244-1254https://doi.org/10.1016/j.jtho.2019.02.009
- Response assessment criteria for brain metastases: proposal from the RANO group.Lancet Oncol. 2015; 16: e270-e278https://doi.org/10.1016/S1470-2045(15)70057-4
- Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.Cancer Discov. 2015; 5: 1164-1177https://doi.org/10.1158/2159-8290.CD-15-0369
- Next-generation sequencing of Stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases.Cancer Discov. 2015; 5: 610-621https://doi.org/10.1158/2159-8290.CD-14-1129
- Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.Nat Genet. 2020; 52: 371-377https://doi.org/10.1038/s41588-020-0592-7
- Associations between single-nucleotide polymorphisms in the PI3K-PTEN-AKT-mTOR pathway and increased risk of brain metastasis in patients with non-small cell lung cancer.Clin Cancer Res. 2013; 19: 6252-6260https://doi.org/10.1158/1078-0432.CCR-13-1093
- Role for loss of nuclear PTEN in a harbinger of brain metastases.J Clin Neurosci. 2017; 44: 148-154https://doi.org/10.1016/j.jocn.2017.06.004
- Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth.Nature. 2015; 527: 100-104https://doi.org/10.1038/nature15376
- The microenvironmental landscape of brain tumors.Cancer Cell. 2017; 31: 326-341https://doi.org/10.1016/j.ccell.2017.02.009
- Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341https://doi.org/10.1038/nature14432
- Pathobiology of brain metastases.J Clin Pathol. 2005; 58: 237-242https://doi.org/10.1136/jcp.2003.013623
- What is immune privilege (not)?.Trends Immunol. 2007; 28: 12-18https://doi.org/10.1016/j.it.2006.11.004
- Immune surveillance of the normal human CNS takes place in dependence of the locoregional blood-brain barrier configuration and is mainly performed by CD3(+)/CD8(+) lymphocytes.Neuropathology. 2011; 31: 230-238https://doi.org/10.1111/j.1440-1789.2010.01167.x
- Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases.Oncoimmunology. 2016; 5e1057388https://doi.org/10.1080/2162402X.2015.1057388
- Characterization of the inflammatory response to solid cancer metastases in the human brain.Clin Exp Metastasis. 2013; 30: 69-81https://doi.org/10.1007/s10585-012-9510-4
- The role of the neural niche in brain metastasis.Clin Exp Metastasis. 2017; 34: 369-376https://doi.org/10.1007/s10585-017-9857-7
- Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases.Oncotarget. 2015; 6: 40836-40849
- Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis.Neuro Oncol. 2017; 19: 1058-1067https://doi.org/10.1093/neuonc/now309
- Contraction of T cell richness in lung cancer brain metastases.Sci Rep. 2018; 8: 2171https://doi.org/10.1038/s41598-018-20622-8
- Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small cell lung cancer.Ann Oncol. 2019; 30: 1521-1530https://doi.org/10.1093/annonc/mdz207
- Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis.Clin Exp Metastasis. 2011; 28: 13-25https://doi.org/10.1007/s10585-010-9354-8
- Astrocytes: biology and pathology.Acta Neuropathol. 2010; 119: 7-35https://doi.org/10.1007/s00401-009-0619-8
- Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis.Am J Pathol. 2010; 176: 2958-2971https://doi.org/10.2353/ajpath.2010.090838
- Astrocyte barriers to neurotoxic inflammation.Nat Rev Neurosci. 2015; 16: 249-263https://doi.org/10.1038/nrn3898
- STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.Nat Med. 2018; 24: 1024-1035https://doi.org/10.1038/s41591-018-0044-4
- Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.Nature. 2016; 533: 493-498https://doi.org/10.1038/nature18268
- Intercellular transfer of small RNAs from astrocytes to lung tumor cells induces resistance to chemotherapy.Oncotarget. 2016; 7: 12489-12504
- Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells.Neuro Oncol. 2014; 16: 1585-1598https://doi.org/10.1093/neuonc/nou128
- Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel.Neuro Oncol. 2016; 18: 486-496https://doi.org/10.1093/neuonc/now037
- Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions.Sci Signal. 2017;10.; https://doi.org/10.1126/scisignal.aai7696
- The myeloid cells of the central nervous system parenchyma.Nature. 2010; 468: 253-262https://doi.org/10.1038/nature09615
- Microglia: a sensor for pathological events in the CNS.Trends Neurosci. 1996; 19: 312-318
- The molecular profile of microglia under the influence of glioma.Neuro Oncol. 2012; 14: 958-978https://doi.org/10.1093/neuonc/nos116
- Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies.Cell Rep. 2016; 17: 2445-2459https://doi.org/10.1016/j.celrep.2016.10.052
- A Combination of Ontogeny and CNS Environment Establishes Microglial Identity.Neuron. 2018; 98e8https://doi.org/10.1016/j.neuron.2018.05.014
- New tools for studying microglia in the mouse and human CNS.Proc Natl Acad Sci U S A. 2016; 113: E1738-E1746https://doi.org/10.1073/pnas.1525528113
- Differential reactions of microglia to brain metastasis of lung cancer.Mol Med. 2006; 12: 161-170https://doi.org/10.2119/2006-00033.He
- Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way.Glia. 2010; 58: 1477-1489https://doi.org/10.1002/glia.21022
- WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.Cell. 2009; 138: 51-62https://doi.org/10.1016/j.cell.2009.04.030
- Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis.Cell Rep. 2019; 27e7https://doi.org/10.1016/j.celrep.2019.03.085
- First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.N Engl J Med. 2017; 376: 2415-2426https://doi.org/10.1056/NEJMoa1613493
- Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater.J Clin Oncol. 2019; 37: 537-546https://doi.org/10.1200/JCO.18.00149
- Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.Lancet. 2019; 393: 1819-1830https://doi.org/10.1016/S0140-6736(18)32409-7
- Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550https://doi.org/10.1016/S0140-6736(15)01281-7
- Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study.Lung Cancer. 2019; 128: 105-112https://doi.org/10.1016/j.lungcan.2018.12.017
- Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA..JCO. 2020; 38 (9501–9501)https://doi.org/10.1200/JCO.2020.38.15_suppl.9501
- Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 924-937https://doi.org/10.1016/S1470-2045(19)30167-6
Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Abreu DR, Hussein M, et al., IMpower131: Final OS results of carboplatin + nab-paclitaxel ± atezolizumab in advanced squamous NSCLC. J Thorac Oncol 2019;14:S243-S4. Abstract OA14.02 https://doi.org/https://doi.org/10.1016/j.jtho.2019.08.484.
Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, et al., IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC. J Thorac Oncol 2018;13:S332 (abstr OA05.07). https://doi.org/10.1016/j.jtho.2018.08.262.
- Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.N Engl J Med. 2019; 381: 2020-2031https://doi.org/10.1056/NEJMoa1910231
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.
