Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Metastasis | Research

Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC

Authors: Jin-Sheng Liu, Yu-Xiang Cai, Yong-Ze He, Jian Xu, Su-Fang Tian, Zhi-Qiang Li

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

Brain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences.

Methods

Seventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases.

Results

In 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335–8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419–10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients.

Conclusions

Both temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.
Appendix
Available only for authorised users
Literature
1.
Arrieta O, Villarreal-Garza C, Zamora J, Blake-Cerda M, de la Mata MD, Zavala DG, Muñiz-Hernández S, de la Garza J. Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiat Oncol. 2011;6:166.PubMedPubMedCentralCrossRef
2.
Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419–25.PubMedCrossRef
3.
4.
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.PubMedCrossRef
5.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):185–S198.CrossRef
6.
7.
Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58–67.PubMedCrossRef
8.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29.PubMedCrossRef
9.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.PubMedPubMedCentralCrossRef
10.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.PubMedPubMedCentralCrossRef
11.
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46.PubMedCrossRef
12.
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot J-M, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046–54.PubMedCrossRef
13.
14.
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.PubMedCrossRef
15.
Sampson JH, Gunn MD, Fecci PE, Ashley DM. Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer. 2020;20(1):12–25.PubMedCrossRef
16.
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–77.PubMedCrossRef
17.
Kontos F, Michelakos T, Kurokawa T, Sadagopan A, Schwab JH, Ferrone CR, Ferrone S. B7-H3: an attractive target for antibody-based immunotherapy. Clin Cancer Res. 2021;27(5):1227–35.PubMedCrossRef
18.
19.
Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;108(13):4118–25.PubMedCrossRef
20.
Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196(4):459–68.PubMedPubMedCentralCrossRef
21.
Miao H, Wang B. EphA receptor signaling–complexity and emerging themes. Semin Cell Dev Biol. 2012;23(1):16–25.PubMedCrossRef
22.
23.
Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133(1):38–52.PubMedCrossRef
24.
Camp RL, Chung GG, Rimm DL. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002;8(11):1323–7.PubMedCrossRef
25.
Xi Y, Zhang T, Sun W, Liang R, Ganesh S, Chen H. GOLM1 and FAM49B: potential biomarkers in HNSCC based on bioinformatics and immunohistochemical analysis. Int J Mol Sci. 2022;23(23).
26.
Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, Molina J, Kim J-H, Arvis CD, Ahn M-J, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.PubMedCrossRef
27.
Pabla S, Conroy JM, Nesline MK, Glenn ST, Papanicolau-Sengos A, Burgher B, Hagen J, Giamo V, Andreas J, Lenzo FL, et al. Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients. J Immunother Cancer. 2019;7(1):27.PubMedPubMedCentralCrossRef
28.
Mansfield AS, Aubry MC, Moser JC, Harrington SM, Dronca RS, Park SS, Dong H. 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(10):1953–8.PubMedPubMedCentralCrossRef
29.
Failing JJ, Aubry MC, Mansfield AS. Human leukocyte antigen expression in paired primary lung tumors and brain metastases in non-small cell lung cancer. Cancer Immunol Immunother. 2021;70(1):215–9.PubMedCrossRef
30.
Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, Wang X. B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer. 2006;53(2):143–51.PubMedCrossRef
31.
Yim J, Koh J, Kim S, Song SG, Ahn HK, Kim YA, Jeon YK, Chung DH. Effects of B7-H3 expression on tumour-infiltrating immune cells and clinicopathological characteristics in non-small-cell lung cancer. Eur J Cancer. 2020;133:74–85.PubMedCrossRef
32.
Kinch MS, Moore M-B, Harpole DH. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res. 2003;9(2):613–8.PubMed
33.
Mandarano M, Bellezza G, Belladonna ML, Van den Eynde BJ, Chiari R, Vannucci J, Mondanelli G, Ludovini V, Ferri I, Bianconi F, et al. Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: an immunohistochemical study with clinicopathological and prognostic implications. Virchows Arch. 2019;474(2):159–68.PubMedCrossRef
34.
Tamminga M, Hiltermann TJN, Schuuring E, Timens W, Fehrmann RS, Groen HJ. Immune microenvironment composition in non-small cell lung cancer and its association with survival. Clin Transl Immunology. 2020;9(6):e1142.PubMedPubMedCentralCrossRef
35.
Desbois M, Udyavar AR, Ryner L, Kozlowski C, Guan Y, Dürrbaum M, Lu S, Fortin J-P, Koeppen H, Ziai J, et al. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat Commun. 2020;11(1):5583.PubMedPubMedCentralCrossRef
36.
Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22(8):1865–74.PubMedCrossRef
37.
Lu BY, Gupta R, Aguirre-Ducler A, Gianino N, Wyatt H, Ribeiro M, Chiang VL, Contessa JN, Adeniran AJ, Jilaveanu LB et al. Spatially resolved analysis of the T cell immune contexture in lung cancer-associated brain metastases. J Immunother Cancer. 2021;9(10).
38.
Kim R, Keam B, Kim S, Kim M, Kim SH, Kim JW, Kim YJ, Kim TM, Jeon YK, Kim D-W, et al. Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors. BMC Cancer. 2019;19(1):19.PubMedPubMedCentralCrossRef
39.
Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, Yu JB, et al. 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(5):655–63.PubMedPubMedCentralCrossRef
40.
Lee K, Choi YJ, Kim JS, Kim DS, Lee SY, Shin BK, Kang EJ. Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications. Thorac Cancer. 2021;12(15):2143–50.PubMedPubMedCentralCrossRef
41.
Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624–33.PubMedCrossRef
42.
Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2).
43.
Li M, Hou X, Sai K, Wu L, Chen J, Zhang B, Wang N, Wu L, Zheng H, Zhang J, et al. Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060). Oncoimmunology. 2022;11(1):2059874.PubMedPubMedCentralCrossRef
44.
Batur S, Dulger O, Durak S, Yumuk PF, Caglar HB, Bozkurtlar E, Bozkurt S, Tastekin E, Cicin I, Ahiskali R, et al. Concordance of PD-L1 expression and CD8 + TIL intensity between NSCLC and synchronous brain metastases. Bosn J Basic Med Sci. 2020;20(3):329–35.PubMedPubMedCentral
45.
Wu J, Sun W, Yang X, Wang H, Liu X, Chi K, Zhou L, Huang X, Mao L, Zhao S, et al. Heterogeneity of programmed death-ligand 1 expression and infiltrating lymphocytes in paired resected primary and metastatic non-small cell lung cancer. Mod Pathol. 2022;35(2):218–27.PubMedCrossRef
46.
Zhou J, Gong Z, Jia Q, Wu Y, Yang Z-Z, Zhu B. Programmed death ligand 1 expression and CD8 + tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer. Biochem Biophys Res Commun. 2018;498(4):751–7.PubMedCrossRef
47.
48.
Li Z-Y, Zhang X-H, Chen Y, Guo J-G, Sai K, Yang Q-Y, Chen Z-P, Mou Y-G. Clinical significance of B7-H4 expression in matched non-small cell lung cancer brain metastases and primary tumors. Onco Targets Ther. 2013;6:869–75.PubMedPubMedCentralCrossRef
49.
Beatty GL, O’Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. 2017;23(13):3269–76.PubMedPubMedCentralCrossRef
50.
Gibney GT, Hamid O, Lutzky J, Olszanski AJ, Mitchell TC, Gajewski TF, Chmielowski B, Hanks BA, Zhao Y, Newton RC, et al. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J Immunother Cancer. 2019;7(1):80.PubMedPubMedCentralCrossRef
51.
Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob J-J, Kim TM, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083–97.PubMedCrossRef
52.
Sondak VK, Khushalani NI. Echoes of a failure: what lessons can we learn? Lancet Oncol. 2019;20(8):1037–9.PubMedCrossRef
53.
Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.PubMedPubMedCentralCrossRef
54.
Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2012;60(3):502–14.PubMedCrossRef
55.
56.
Kudo Y, Haymaker C, Zhang J, Reuben A, Duose DY, Fujimoto J, Roy-Chowdhuri S, Solis Soto LM, Dejima H, Parra ER, et al. Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer. Ann Oncol. 2019;30(9):1521–30.PubMedPubMedCentralCrossRef
57.
Müller A, Brandenburg S, Turkowski K, Müller S, Vajkoczy P. Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells. Int J Cancer. 2015;137(2):278–88.PubMedCrossRef
58.
Mirzaei R, Yong VW. Microglia-T cell conversations in brain cancer progression. Trends Mol Med. 2022;28(11):951–63.PubMedCrossRef
59.
Müller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, Watchmaker PB, Yagnik G, Di Lullo E, Malatesta M, et al. Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol. 2017;18(1):234.PubMedPubMedCentralCrossRef
60.
Gabrusiewicz K, Rodriguez B, Wei J, Hashimoto Y, Healy LM, Maiti SN, Thomas G, Zhou S, Wang Q, Elakkad A et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight. 2016;1(2).
61.
Takashima Y, Kawaguchi A, Kanayama T, Hayano A, Yamanaka R. Correlation between lower balance of Th2 helper T-cells and expression of PD-L1/PD-1 axis genes enables prognostic prediction in patients with glioblastoma. Oncotarget. 2018;9(27):19065–78.PubMedPubMedCentralCrossRef
62.
Takashima Y, Kawaguchi A, Hayano A, Yamanaka R. CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme. PLoS ONE. 2019;14(5):e0216825.PubMedPubMedCentralCrossRef
63.
Takashima Y, Kawaguchi A, Sato R, Yoshida K, Hayano A, Homma J, Fukai J, Iwadate Y, Kajiwara K, Ishizawa S, et al. Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL. Sci Rep. 2019;9(1):10004.PubMedPubMedCentralCrossRef
Metadata
Title
Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC
Authors
Jin-Sheng Liu
Yu-Xiang Cai
Yong-Ze He
Jian Xu
Su-Fang Tian
Zhi-Qiang Li
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-11875-w

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue

Research

MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma

Research

Expression level and clinical significance of NBAT-1 in human cancers: a systematic review and meta-analysis

Research

Pancreatic adenocarcinoma third line systemic treatments: a retrospective cohort study

Research

The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.

Research

Association of hormone receptors and human epidermal growth factor receptor-2/neu expressions with clinicopathologic factors of breast carcinoma: a cross-sectional study in a tertiary care hospital, Kabul, Afghanistan

Research

Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits