Immune overdrive signature in colorectal tumor subset predicts poor clinical outcome
Marwan Fakih, … , Jeffrey A. Longmate, Peter P. Lee
Marwan Fakih, … , Jeffrey A. Longmate, Peter P. Lee
Published September 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4464-4476. https://doi.org/10.1172/JCI127046.
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Research Article Immunology Oncology

Immune overdrive signature in colorectal tumor subset predicts poor clinical outcome

Abstract

The prognostic value of immune cell infiltration within the tumor microenvironment (TME) has been extensively investigated via histological and genomic approaches. Based on the positive prognostic value of T cell infiltration, Immunoscore has been developed and validated for predicting risk of recurrence for colorectal cancer (CRC). Also, association between a consensus T helper 1 (Th-1) immune response and favorable clinical outcomes has been observed across multiple cancer types. Here, we reanalyzed public genomic data sets from The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (NCBI-GEO) and performed multispectral immunohistochemistry (IHC) on a cohort of colorectal tumors. We identified and characterized a risk group, representing approximately 10% of CRC patients, with high intratumoral CD8+ T cell infiltration, but poor prognosis. These tumors included both microsatellite instable (MSI) and stable (MSS) phenotypes and had a high density of tumor-associated macrophages (TAMs) that expressed CD274 (programmed death-ligand 1 [PD-L1]), TGF-β activation, and an immune overdrive signature characterized by the overexpression of immune response and checkpoint genes. Our findings illustrate that CRC patients may have poor prognosis despite high CD8+ T cell infiltration and provide CD274 as a simple biomarker for identifying these patients.

Authors

Marwan Fakih, Ching Ouyang, Chongkai Wang, Travis Yiwey Tu, Maricel C. Gozo, May Cho, Marvin Sy, Jeffrey A. Longmate, Peter P. Lee

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Figure 2

Prognostic significance of CD274 is dependent on CD8A gene expression levels in CRC.

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Prognostic significance of CD274 is dependent on CD8A gene expression le...
The log-rank test score at each candidate cut-off across the log-transformed CD274 gene expression values was plotted (A). A bimodal score distribution was observed, and 2 cut-offs (indicated with blue and red arrows) were tested for dichotomizing the patients for survival analysis (as shown in Figure 1 and Supplemental Figure 2). Scatter plots of log2-transformed CD8A and CD274 gene expression values are shown for TCGA data set (B and D). Median value of CD8A expression was applied to test prognostic significance of CD274 expression in CD8Alo (B) and CD8Ahi (D) populations (n = 299 and 300, respectively; boxed by blue lines). Kaplan-Meier survival curves are plotted (C and E) for the risk groups stratified by optimal CD274 cut-offs shown (B and D). THe log-rank test P values are shown for each plot.