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. 2019 Mar 1;25(5):1526-1534.
doi: 10.1158/1078-0432.CCR-18-2013. Epub 2018 Sep 10.

Spatial Architecture and Arrangement of Tumor-Infiltrating Lymphocytes for Predicting Likelihood of Recurrence in Early-Stage Non-Small Cell Lung Cancer

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Spatial Architecture and Arrangement of Tumor-Infiltrating Lymphocytes for Predicting Likelihood of Recurrence in Early-Stage Non-Small Cell Lung Cancer

Germán Corredor et al. Clin Cancer Res. .

Abstract

Purpose: The presence of a high degree of tumor-infiltrating lymphocytes (TIL) has been proven to be associated with outcome in patients with non-small cell lung cancer (NSCLC). However, recent evidence indicates that tissue architecture is also prognostic of disease-specific survival and recurrence. We show a set of descriptors (spatial TIL, SpaTIL) that capture density, and spatial colocalization of TILs and tumor cells across digital images that can predict likelihood of recurrence in early-stage NSCLC.

Experimental design: The association between recurrence in early-stage NSCLC and SpaTIL features was explored on 301 patients across four different cohorts. Cohort D1 (n = 70) was used to identify the most prognostic SpaTIL features and to train a classifier to predict the likelihood of recurrence. The classifier performance was evaluated in cohorts D2 (n = 119), D3 (n = 112), and D4 (n = 112). Two pathologists graded each sample of D1 and D2; intraobserver agreement and association between manual grading and likelihood of recurrence were analyzed.

Results: SpaTIL was associated with likelihood of recurrence in all test sets (log-rank P < 0.02). A multivariate Cox proportional hazards analysis revealed an HR of 3.08 (95% confidence interval, 2.1-4.5, P = 7.3 × 10-5). In contrast, agreement among expert pathologists using tumor grade was moderate (Kappa = 0.5), and the manual TIL grading was only prognostic for one reader in D2 (P = 8.0 × 10-3).

Conclusions: A set of features related to density and spatial architecture of TILs was found to be associated with a likelihood of recurrence of early-stage NSCLC. This information could potentially be used for helping in treatment planning and management of early-stage NSCLC.See related commentary by Peled et al., p. 1449.

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Conflict of interest statement

Disclosure of Conflicts of Interest: A. Madabhushi: Inspirata-Stock Options/Consultant/Scientific Advisory Board Member, NIH Academic-Industry Partnership grants, Sponsored Research, Elucid Bioimaging Inc.-Stock Options, PathCore Inc-NIH Academic Industrial Partnership, Philips – Sponsored Research. D. L. Rimm: Consultant or advisor to Astra Zeneca, Agendia, Agilent, Biocept, BMS, Cell Signaling Technology, Cepheid, Merck, Perkin Elmer, PAIGE, and Ultivue; equity in PixelGear; Astra Zeneca, Cepheid, Navigate/Novartis, NextCure, Lilly, Ultivue, and Perkin Elmer fund research in his lab. K. A. Schalper: Speaker for Takeda, Merck; Consultant for Moderna, Celgene, Shattuck Labs; Research funding from: Genoptix (Novartis), Vasculox/Tioma, Tesaro, Onkaido, Takeda, Surface Oncology, Pierre Fabre.

Figures

Figure 1.
Figure 1.
Representative TMA tissue spots of recurrent (top row) and non-recurrent (bottom row) early-stage NSCLC cases. The first column (a, d) shows the original H&E-stained images. Identification of TILs (yellow) and non-TILs (cyan) is presented in the second column (b, e). The third column (c, f) illustrates the qualitative representation of one of the SpaTIL features overlaid on the original images, specifically, the variation in the density of lymphocyte clusters. The color bars represent the density measurement (H stands for highly dense clusters while L stands for low-density or sparse clusters). Non-recurrence cases are characterized by the presence of more high-density clusters while recurrence cases were comprised of a larger number of low-density clusters.
Figure 2.
Figure 2.
Prognostic prediction results for human readers, QD, and QS for D1. a) Bar plot illustrating the Kappa index and correlation coefficient computed between readers 1 and 2, b) Kaplan-Meier curves for readers 1 and 2, c) ROC curve and corresponding CI for QS, d) Kaplan-Meier plot for QS classifier using recurrence free survival as endpoint, e) Kaplan-Meier plot for QD classifier. The number of cases in each category is indicated in the charts.
Figure 3.
Figure 3.
Prognostic prediction results for human readers, QD, and QS for D2. a) Bar plot illustrating the Kappa index and correlation coefficient computed between readers 1 and 2, b) Kaplan-Meier curves for readers 1 and 2, c) ROC curve and corresponding CI for QS, d) Kaplan-Meier plot for QS classifier using recurrence free survival as endpoint, e) Kaplan-Meier plot for QD classifier. The number of cases in each category is indicated in the charts.
Figure 4.
Figure 4.
Prognostic prediction results for QD and QS for D3 (top row) and D4 (bottom row). First column (a, d) shows the ROC curve and corresponding CI for QS, second column (b, e) presents the Kaplan-Meier plots for QS classifier using recurrence free survival as endpoint, and third column (c, f) illustrates the Kaplan-Meier plot for QD classifier. The number of cases in each category is indicated in the charts.

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References

    1. Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, et al. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis. Cellular Physiology and Biochemistry 2015;37:1560–1571. - PubMed
    1. Bremnes RM, Donnem T, Busund LT. Importance of tumor infiltrating lymphocytes in non-small cell lung cancer? Annals of Translational Medicine 2016;4. - PMC - PubMed
    1. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Translational Lung Cancer Research 2014;3. - PMC - PubMed
    1. Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, et al. Objective Measurement and Clinical Significance of TILs in Non–Small Cell Lung Cancer. Journal of the National Cancer Institute 2015;107. - PMC - PubMed
    1. Donnem T, Hald SM, Paulsen EE, Richardsen E, Al-Saad S, Kilvaer TK, et al. Stromal CD8+ T-cell Density - A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer. Clinical Cancer Research 2015;21:2635–2643. - PubMed

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