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FIGURE 4 from Peritumoral Immune-suppressive Mechanisms Impede Intratumoral Lymphocyte Infiltration into Colorectal Cancer Liver versus Lung Metastases

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posted on 2023-10-12, 14:20 authored by Jian Ye, Weihua Guo, Chongkai Wang, Colt A. Egelston, Massimo D'Apuzzo, Geereesh Shankar, Marwan G. Fakih, Peter P. Lee

Higher antigen presentation potential in lung metastases. A, Correlations of the immune cell density between histologic regions. PCC were calculated from the density of each immune cell type in different histologic regions. B, Representative images of primary and metastatic colorectal cancer tumors stained with mIF panel 4. The cancer cells, TCF1+ CD4 T cells, stem-like CD8 T cells and APCs were color coded and identified as Fig. 1C. The yellow dash lines indicate the boundaries between inner and outer invasive margin. C, Mean number of TCF1+ CD4 T cells and stem-like CD8 T cells around 10 µm radius of APCs and mean number of APCs around 10 µm radius of TCF1+ CD4 T cells and stem-like CD8 T cells. D, Paired comparison of cell density between each two organs in the different histologic regions. Statistical significance was determined by Wilcoxon signed-rank test. E, GSEA of liver and lung metastases samples from GES48468. Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to determine significantly modified pathways. Bars in red and blue represent, respectively, a positive and negative enrichment in the associated pathway. The x axis shows the normalized enrichment score (NES) of the analysis, and the y axis the enriched pathways. F, Heat map of top genes differentially expressed in GES48468 primary and metastatic colorectal cancer tumor samples from KEGG_ANITGENE_PROCESSING_AND_PRESENTATION pathway.

Funding

HHS | NIH | National Cancer Institute (NCI)

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ARTICLE ABSTRACT

Patients with microsatellite stable (MSS) colorectal cancer with liver metastases are resistant to immune checkpoint inhibitor (ICI) therapy, while about one-third of patients with colorectal cancer without liver metastases, particularly those with lung-only metastases, respond to ICI. We analyzed primary colorectal cancer tumors and major metastatic sites (liver, lung, peritoneal) using multiplex immunofluorescence and whole-slide spatial analyses to identify variations in immune contexture and regional localization within the tumor microenvironment. While levels of T and B cells within peritumoral regions were similar, their levels were significantly lower within the tumor core of liver and peritoneal metastases compared with lung metastases. In contrast, antigen-presenting cells (APC) and APC–T cell interactions were more abundant in all regions of lung metastases. We also identified an abundance of lymphoid aggregates throughout lung metastases, but these were present only within peritumoral regions of liver and peritoneal metastases. Larger lymphoid aggregates consistent with features of tertiary lymphoid structures were observed within or adjacent to primary tumors, but not metastatic lesions. Our findings were validated using NanoString GeoMx DSP, which further showed that liver metastases had higher expression of immune-suppressive markers, while lung metastases showed higher proinflammatory activity and T-cell activation markers. Peritoneal metastases demonstrated higher expression of cancer-associated fibroblast–related proteins and upregulated PD-1/PD-L1 signaling molecules. Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites. These findings suggest that metastatic site–dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer. Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site–dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.