Background

We have previously reported significant differences between the tumor immune microenvironment (TIME) of primary colorectal cancer (CRC-P) and different metastatic sites. Increased immune cell infiltration, B-cells, and CD8 cells and decreased macrophages were noted in CRC-P and lung metastatic (LuM) lesions compared to liver (LM) and peritoneum (PM) metastases. We expanded our work to MSI CRC and compared their TIME to respective MSS tumor sites.

Methods

De-identified cases of MSS and MSI metastatic CRC that underwent next-generation sequencing with the Tempus xT assay were selected from the Tempus Database. Gene expression patterns of immune cells, including B, T (CD4+, CD8+), NK cells, and macrophages, were used to predict relative intra-tumor abundance. MSI and MSS cohorts included CRC-P, LM, and PM. LuM was analyzed only in MSS tumors due to the limited number of MSI LuM. Tumor mutational burden (TMB), neoantigen burden, and proportion of immune cells in CRC-P, LM, and PM were compared across MSI and MSS patients. Chi-squared/Fischer’s exact tests or Kruskal-Wallis tests were used to assess statistical significance.

Results

A total of 208 MSI and 6,732 MSS tumors were subject of analysis. No differences were noted in TMB, neoantigen load, or PD-L1 expression between MSI CRC-P, LM, or PM. Across the 3 tissue groups, the median TMB and neoantigen tumor burden were significantly higher in MSI cohorts when compared to MSS cohorts (p<0.001). Compared to MSS LM, MSI LM exhibited a higher percentage of CD8 cells (p=0.002) and NK cells (p<0.001), with a trend towards a lower percentage of macrophages (p=0.14). Similar differences were noted for MSI PM compared to MSS PM (CD8 cells p=0.018, NK cells p=0.044 and macrophages p=0.023). The TIME of MSS LuM lesions shared more similarities with that of MSI LM/PM than MSS LM/PM.

Conclusions

MSI LM and PM have a more favorable TIME than respective MSS metastases, explaining the discordance in response to checkpoint inhibitors (CPI) and reported CPI benefits in MSI cases across all metastatic sites. MSS LuM have a comparable TIME to MSI metastatic sites, explaining the recently reported benefits from CPI therapy in this group.

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