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Erschienen in: European Radiology 12/2022

31.05.2022 | Imaging Informatics and Artificial Intelligence

Development and validation of a computed tomography–based immune ecosystem diversity index as an imaging biomarker in non-small cell lung cancer

verfasst von: Lan He, Zhen-Hui Li, Li-Xu Yan, Xin Chen, Sebastian Sanduleanu, Wen-Zhao Zhong, Phillippe Lambin, Zhao-Xiang Ye, Ying-Shi Sun, Yu-Lin Liu, Jin-Rong Qu, Lin Wu, Chang-Ling Tu, Madeleine Scrivener, Thierry Pieters, Emmanuel Coche, Qian Yang, Mei Yang, Chang-Hong Liang, Yan-Qi Huang, Zai-Yi Liu

Erschienen in: European Radiology | Ausgabe 12/2022

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Abstract

Objectives

To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction.

Methods

In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3+, CD4+, and CD8+ T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55).

Results

iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759–0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647–0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206–0.546, p < 0.001), Resec4 (0.199, 0.040–1.000, p < 0.001), and TCIA (0.303, 0.098–0.944, p = 0.001).

Conclusions

iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection.

Key Points

• Decoding tumour immune microenvironment enables advanced biomarkers identification.
• Immune ecosystem diversity index characterises intratumoural immune status noninvasively.
• Immune ecosystem diversity index is prognostic for NSCLC patients.
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Literatur
1.
2.
Zurück zum Zitat Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A (2010) AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A (2010) AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York
3.
Zurück zum Zitat Donnem T, Hald SM, Paulsen EE et al (2015) Stromal CD8+ T-cell density-a promising supplement to TNM staging in non-small cell lung cancer. Clin Cancer Res 21(11):2635–2643CrossRefPubMed Donnem T, Hald SM, Paulsen EE et al (2015) Stromal CD8+ T-cell density-a promising supplement to TNM staging in non-small cell lung cancer. Clin Cancer Res 21(11):2635–2643CrossRefPubMed
4.
Zurück zum Zitat Donnem T, Kilvaer TK, Andersen S et al (2016) Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol 27(2):225–232CrossRefPubMed Donnem T, Kilvaer TK, Andersen S et al (2016) Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol 27(2):225–232CrossRefPubMed
5.
Zurück zum Zitat Junttila MR, de Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501(7467):346–354CrossRefPubMed Junttila MR, de Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501(7467):346–354CrossRefPubMed
6.
Zurück zum Zitat Natrajan R, Sailem H, Mardakheh FK et al (2016) Microenvironmental heterogeneity parallels breast cancer progression: a histology-genomic integration analysis. PLoS Med 13(2):e1001961CrossRefPubMedPubMedCentral Natrajan R, Sailem H, Mardakheh FK et al (2016) Microenvironmental heterogeneity parallels breast cancer progression: a histology-genomic integration analysis. PLoS Med 13(2):e1001961CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Binnewies M, Roberts EW, Kersten K et al (2018) Understanding the tumour immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–350 Binnewies M, Roberts EW, Kersten K et al (2018) Understanding the tumour immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–350
8.
Zurück zum Zitat Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cance 12(4):298–306CrossRef Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cance 12(4):298–306CrossRef
9.
Zurück zum Zitat Bremnes RM, Busund LT, Kilvaer TL et al (2016) The role of tumour-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol 11(6):789–800 Bremnes RM, Busund LT, Kilvaer TL et al (2016) The role of tumour-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol 11(6):789–800
10.
Zurück zum Zitat Galon J, Mlecnik B, Bindea G et al (2014) Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 232(2):199–209CrossRefPubMed Galon J, Mlecnik B, Bindea G et al (2014) Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 232(2):199–209CrossRefPubMed
11.
Zurück zum Zitat Sun R, Limkin EJ, Vakalopoulou M et al (2018) A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Lancet Oncol 19(9):1180–1191CrossRefPubMed Sun R, Limkin EJ, Vakalopoulou M et al (2018) A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Lancet Oncol 19(9):1180–1191CrossRefPubMed
12.
Zurück zum Zitat Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128CrossRefPubMedPubMedCentral Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571CrossRefPubMedPubMedCentral Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567CrossRefPubMedPubMedCentral Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Li B, Cui Y, Diehn M, Li R (2017) Development and validation of an individualized immune prognostic signature in early-stage nonsquamous non-small cell lung cancer. JAMA Oncol 3(11):1529–1537CrossRefPubMedPubMedCentral Li B, Cui Y, Diehn M, Li R (2017) Development and validation of an individualized immune prognostic signature in early-stage nonsquamous non-small cell lung cancer. JAMA Oncol 3(11):1529–1537CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Steele KE, Tan TH, Korn R et al (2018) Measuring multiple parameters of CD8+ tumour-infiltrating lymphocytes in human cancers by image analysis. J Immunother Cancer 6(1):20 Steele KE, Tan TH, Korn R et al (2018) Measuring multiple parameters of CD8+ tumour-infiltrating lymphocytes in human cancers by image analysis. J Immunother Cancer 6(1):20
17.
Zurück zum Zitat Yan X, Jiao SC, Zhang GQ, Guan Y, Wang JL (2017) Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer. Cancer Gene Ther 24(2):57–63CrossRefPubMedPubMedCentral Yan X, Jiao SC, Zhang GQ, Guan Y, Wang JL (2017) Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer. Cancer Gene Ther 24(2):57–63CrossRefPubMedPubMedCentral
18.
19.
20.
Zurück zum Zitat Aerts HJ, Velazquez ER, Leijenaar RT et al (2014) Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 5:4006CrossRefPubMed Aerts HJ, Velazquez ER, Leijenaar RT et al (2014) Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 5:4006CrossRefPubMed
22.
Zurück zum Zitat Heagerty PJ, Lumley T, Pepe MS (2000) Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 56(2):337–344CrossRefPubMed Heagerty PJ, Lumley T, Pepe MS (2000) Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 56(2):337–344CrossRefPubMed
23.
Zurück zum Zitat Fraley C, Raftery AE (2002) Model-based clustering, discriminant analysis, and density estimation. Journal of the American Statistical Association 97(458):611–631CrossRef Fraley C, Raftery AE (2002) Model-based clustering, discriminant analysis, and density estimation. Journal of the American Statistical Association 97(458):611–631CrossRef
24.
Zurück zum Zitat El Naqa I, Ten Haken RK (2018) Can radiomics personalise immunotherapy? Lancet Oncol 19(9):1138–1139CrossRefPubMed El Naqa I, Ten Haken RK (2018) Can radiomics personalise immunotherapy? Lancet Oncol 19(9):1138–1139CrossRefPubMed
25.
Zurück zum Zitat Maley CC, Koelble K, Natrajan R, Aktipis A, Yuan Y (2015) An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer. Breast Cancer Res 17(1):131CrossRefPubMedPubMedCentral Maley CC, Koelble K, Natrajan R, Aktipis A, Yuan Y (2015) An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer. Breast Cancer Res 17(1):131CrossRefPubMedPubMedCentral
26.
27.
Zurück zum Zitat Pienta KJ, McGregor N, Axelrod R, Axelrod DE (2008) Ecological therapy for cancer: defining tumours using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol 1(4):158–164 Pienta KJ, McGregor N, Axelrod R, Axelrod DE (2008) Ecological therapy for cancer: defining tumours using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol 1(4):158–164
28.
Zurück zum Zitat Merlo LM, Pepper JW, Reid BJ, Maley CC (2016) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6(12):924–935CrossRef Merlo LM, Pepper JW, Reid BJ, Maley CC (2016) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6(12):924–935CrossRef
29.
Zurück zum Zitat Zwanenburg A, Vallières M, Abdalah MA et al (2020) The image biomarker standardization initiative: standardized quantitative radiomics for high-throughput image-based phenotyping. Radiology 295(2):328–338 Zwanenburg A, Vallières M, Abdalah MA et al (2020) The image biomarker standardization initiative: standardized quantitative radiomics for high-throughput image-based phenotyping. Radiology 295(2):328–338
30.
Zurück zum Zitat Tang C, Hobbs B, Amer A et al (2018) Development of an immune-pathology informed radiomics model for non-small cell lung cancer. Sci Rep 8(1):1922CrossRefPubMedPubMedCentral Tang C, Hobbs B, Amer A et al (2018) Development of an immune-pathology informed radiomics model for non-small cell lung cancer. Sci Rep 8(1):1922CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Aerts HJ (2016) The Potential of Radiomic-Based Phenotyping in Precision Medicine: a Review. JAMA Oncol 2(12):1636–1642CrossRefPubMed Aerts HJ (2016) The Potential of Radiomic-Based Phenotyping in Precision Medicine: a Review. JAMA Oncol 2(12):1636–1642CrossRefPubMed
32.
Zurück zum Zitat Jiang Y, Wang H, Wu J et al (2020) Noninvasive imaging evaluation of tumour immune microenvironment to predict outcomes in gastric cancer. Ann Oncol 31(6):760–768 Jiang Y, Wang H, Wu J et al (2020) Noninvasive imaging evaluation of tumour immune microenvironment to predict outcomes in gastric cancer. Ann Oncol 31(6):760–768
33.
Zurück zum Zitat Rakaee M, Kilvaer TK, Dalen SM et al (2018) Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer. Hum Pathol 79:188–198 Rakaee M, Kilvaer TK, Dalen SM et al (2018) Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer. Hum Pathol 79:188–198
35.
Zurück zum Zitat Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271CrossRefPubMed Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271CrossRefPubMed
36.
Zurück zum Zitat Ferris RL, Galon J (2016) Additional support for the introduction of immune cell quantification in colorectal cancer classification. J Natl Cancer Inst 108(8):djw033. Ferris RL, Galon J (2016) Additional support for the introduction of immune cell quantification in colorectal cancer classification. J Natl Cancer Inst 108(8):djw033.
37.
Zurück zum Zitat Ascierto PA, Capone M, Urba WJ et al (2013) The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J Transl Med 11:54CrossRefPubMedPubMedCentral Ascierto PA, Capone M, Urba WJ et al (2013) The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J Transl Med 11:54CrossRefPubMedPubMedCentral
Metadaten
Titel
Development and validation of a computed tomography–based immune ecosystem diversity index as an imaging biomarker in non-small cell lung cancer
verfasst von
Lan He
Zhen-Hui Li
Li-Xu Yan
Xin Chen
Sebastian Sanduleanu
Wen-Zhao Zhong
Phillippe Lambin
Zhao-Xiang Ye
Ying-Shi Sun
Yu-Lin Liu
Jin-Rong Qu
Lin Wu
Chang-Ling Tu
Madeleine Scrivener
Thierry Pieters
Emmanuel Coche
Qian Yang
Mei Yang
Chang-Hong Liang
Yan-Qi Huang
Zai-Yi Liu
Publikationsdatum
31.05.2022
Verlag
Springer Berlin Heidelberg
Erschienen in
European Radiology / Ausgabe 12/2022
Print ISSN: 0938-7994
Elektronische ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-022-08873-6

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