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. 2020 Apr;8(1):e000205.
doi: 10.1136/jitc-2019-000205.

Development and Validation of the Immune Signature to Predict Distant Metastasis in Patients With Nasopharyngeal Carcinoma

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Free PMC article

Development and Validation of the Immune Signature to Predict Distant Metastasis in Patients With Nasopharyngeal Carcinoma

Sai-Lan Liu et al. J Immunother Cancer. .
Free PMC article

Abstract

Background: The tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC).

Methods: Using multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients.

Results: Eight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed.

Conclusions: The immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT.

Keywords: immunology; oncology; pathology; tumors.

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Workflow of the present study. (A) Process of multiplexed immunofluorescence staining and image analysis. (B) Study flow. (C) Example of a 2×2 correlation of the immune signature in the intratumor between two continuous sections of TMAs (r=0.988). (D) Scatter diagram illustrating the immune signature A of the training and validation cohorts. Statistical comparison was performed by first testing normality using the Kolmogorov-Smirnov test, and then the Mann-Whitney non-parametric test was used to compare the two groups. LASSO, least absolute shrinkage and selection operator; NPC, nasopharyngeal carcinoma; TMA, tissue microarray; TSA, tyramide signal amplification.
Figure 2
Figure 2
Kaplan-Meier curves for distant metastasis-free survival and progression-free survival between the immune signature-defined high-risk and low-risk groups in the training and validation cohorts.
Figure 3
Figure 3
Kaplan-Meier survival curves between IC+CCRT and CCRT alone in different groups. Distant metastasis-free survival (A) and progression-free survival (B) for the whole combined cohort; distant metastasis-free survival (C) and progression-free survival (D) for the immune signature-defined low-risk patients in the combined cohort; distant metastasis-free survival (E) and progression-free survival (F) for the immune signature-defined high-risk patients in the combined cohort. We calculated p values using the unadjusted log-rank test and HRs using a univariate Cox regression analysis. CCRT, concurrentchemoradiotherapy; IC, induction chemotherapy.
Figure 4
Figure 4
Nomogram A to predict the risk of distant metastasis in nasopharyngeal carcinoma (A). Calibration curves of the nomogram to predict DMFS at 5 years in: (B) the training cohort and (C) the external validation cohort. The actual DMFS was plotted on the y-axis and the nomogram predicted probability was plotted on the x-axis. HGB, hemoglobin; DMFS, distant metastasis-free survival.

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