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 October 1, 2019; First 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 4

Histological analysis of archival CRC tumors.

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Histological analysis of archival CRC tumors. (A) Representative multipl...
(A) Representative multiplex fluorescent image of a stage III colorectal tumor using a panel of markers including CD8, PD-1, CD274, KRT20 (CK20), and DAPI on FFPE tumor specimen in a City of Hope cohort (n = 71). Original magnification, ×200. (B) Scatter plot of log2-transformed CD8 and CD274 (Stroma) cell density (cells/mm2) across the entire cohort. Median values of CD8 and CD274 cell density are indicated with solid blue and dashed gray lines, respectively, along with relapse and MMR status. CD68+ TAM infiltration and the CD274 expression among CRC risk groups were quantified using a second panel of markers, including CD68 (representative images shown in Supplemental Figure 4). Standard boxplots (horizontal lines at the 25th percentile, the median, and the 75th percentile) are applied to visualize the distribution of log2-transformed cell density (cells/mm2) of (C) CD68+ macrophages, (E) CD274+CD68+ macrophages, and (F) CD274–CD68+ macrophages across the 3 observed risk groups. Fraction of CD68+ macrophages with CD274 expression for samples across the 3 observed risk groups is compared in D. MMR-deficient (black triangles) and -proficient (gray circles) samples are labeled. 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.