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 1

Comparison of TME stratification based on CD8A and CD274 gene expression between TCGA melanoma and CRC.

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Comparison of TME stratification based on CD8A and CD274 gene expression...
Scatter plots of log2-transformed CD8A and CD274 gene expression values are shown (A and C) for melanoma (n = 459) and CRC (n = 599), respectively. A linear regression line is plotted with the gray shaded region showing the 95% confidence interval. Pearson’s correlation coefficient r and P values are given at the bottom. MSI (black triangles) and MSS (gray circles) statuses are labeled for CRC samples. Median values of CD8A and CD274 expression are indicated with dashed gray lines. log-rank statistics were applied to identify the optimal cut-off for transforming the continuous variable of gene expression into categorical high- and low-expression groups in a survfit model. The test score at each candidate cut-off across the log-transformed gene expression values was plotted. The highest test score (indicated with a blue arrow) was applied for best separating patients into 4 different risk groups (using solid blue lines; named groups I to IV). To compare risk groups between melanoma and CRC, we also applied a secondary peak of test scores (red arrow with an asterisk, which revealed a reverse pattern of survival in CRC as shown in Supplemental Figure 2) for CD274 stratification (indicated with a solid red line instead of a blue line; named groups I, II, III* and IV*). Each stratified risk group is labeled with its population fraction in percentages. Kaplan-Meier survival curves for the 4 risk groups are plotted for melanoma (B) and CRC (D and E). The log-rank test P values are shown for each plot.