Background: We previously demonstrated differences in responses to checkpoint inhibitors between liver and non-liver metastases (mets) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Here, we investigate differences in tumor microenvironment (TME) and mutational landscape of primary and mCRC sites.
Methods: We used the Tempus clinicogenomic database to select de-identified cases of MSS mCRC which underwent Tempus xT testing. Tempus xT is a 648-gene NGS panel that detects somatic alterations and includes RNA sequencing. Gene expression patterns of different immune cells were used to predict their relative abundance within the tumor. Analyzed tumors were divided into 4 categories based: primary tumor (colon), liver, lung, and peritoneal mets. Demographics, genomic alterations, tumor mutational burden (TMB), PD-L1 expression, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared between all 4 categories. Chi-squared/Fisher’s exact tests or Kruskal-Wallis tests were used to assess statistical significance.
Results: Genomic profiles from 4,345 unique mCRC patients were analyzed (Primary CRC = 1734; Liver = 1825; Lung = 443; Peritoneal = 343). Median TMB and PD-L1 expressions had small differences across sites that were statistically significant. KRAS mutations were more frequent and SMAD4 mutations were less prevalent in lung mets. RNA-Seq revealed significant differences in immune cell composition. Lung mets exhibited a higher percentage of B cells and lower percentage of macrophages than liver and peritoneum (p< 0.001), similar to primary tumors. CD4+ T cells were highest in primary tumors, whereas CD8+ T cells were highest in lung mets (p < 0.001).
Conclusions: The TME of lung mets has a more favorable immune composition (increased CD8+ T cells and B cells, decreased macrophages) than that of liver and peritoneal mets, suggesting that MSS mCRC to the lung may potentially be more responsive to immunotherapy.
Immune cells by RNA analysis.
| Characteristic |
Overall, n=4,3451 |
Colon, n=1,7341 |
Liver, n=1,8251 |
Lung, n=4431 |
Peritoneum, n=3431 |
p-value2 |
| % IC of all cells |
0.14 (0.09, 0.19) |
0.13 (0.08, 0.17) |
0.14 (0.09, 0.19) |
0.20 (0.14, 0.24) |
0.14 (0.10, 0.20) |
<0.001 |
| % B cells of all IC |
0.12 (0.05, 0.22) |
0.21 (0.13, 0.30) |
0.06 (0.01, 0.11) |
0.16 (0.10, 0.23) |
0.10 (0.04, 0.17) |
<0.001 |
| % CD4+ T cells of all IC |
0.28 (0.19, 0.37) |
0.32 (0.25, 0.40) |
0.25 (0.16, 0.34) |
0.27 (0.21, 0.34) |
0.24 (0.17, 0.31) |
<0.001 |
| % CD8+ T cells of all IC |
0.03 (0.00, 0.09) |
0.03 (0.00, 0.07) |
0.03 (0.00, 0.09) |
0.07 (0.02, 0.10) |
0.05 (0.00, 0.10) |
<0.001 |
| % macrophages of all IC |
0.39 (0.28, 0.53) |
0.29 (0.20, 0.38) |
0.51 (0.40, 0.62) |
0.34 (0.27, 0.41) |
0.48 (0.37, 0.60) |
<0.001 |
| % NK cells of all IC |
0.10 (0.07, 0.15) |
0.11 (0.07, 0.14) |
0.10 (0.07, 0.15) |
0.13 (0.09, 0.17) |
0.09 (0.06, 0.13) |
<0.001 |
IC = Immune Cells; 1Median (IQR); 2 Kruskal-Wallis rank sum test.
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