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 5

Comparisons of total immune infiltrates and expression levels of cancer cell and representative checkpoint markers across the CRC OS risk groups in TCGA and NCBI-GEO GSE39582 stage II and III samples.

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Comparisons of total immune infiltrates and expression levels of cancer ...
Standard boxplots (horizontal lines at the 25th percentile, the median, and the 75th percentile) are applied to visualize total immune infiltrates and overall gene expression of cancer cells and representative checkpoint markers for each risk group, with MSI (black triangles) and MSS (gray circles) samples labeled. Total immune infiltrates estimated by the tumor deconvolution algorithm CIBERSORT (sum of absolute scores across 22 immune cell types) are shown in panels A and B. KRT20 is applied to represent CRC cells (C and D), and CTLA4 represents immune checkpoint genes (E and F). Statistical P values between groups were determined by Welch’s t tests after Bonferroni’s correction for multiple comparisons: ***P < 0.001, **P < 0.01, *P < 0.05. (A, C, and E) TCGA, n = 391; (B, D, and F) NCBI-GEO GSE39582, n = 461.