Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability

Abstract

Microsatellite instability in colorectal cancer predicts favorable outcomes. However, the mechanistic relationship between microsatellite instability, tumor-infiltrating immune cells, Immunoscore, and their impact on patient survival remains to be elucidated. We found significant differences in mutational patterns, chromosomal instability, and gene expression that correlated with patient microsatellite instability status. A prominent immune gene expression was observed in microsatellite-instable (MSI) tumors, as well as in a subgroup of microsatellite-stable (MSS) tumors. MSI tumors had increased frameshift mutations, showed genetic evidence of immunoediting, had higher densities of Th1, effector-memory T cells, in situ proliferating T cells, and inhibitory PD1-PDL1 cells, had high Immunoscores, and were infiltrated with mutation-specific cytotoxic T cells. Multivariate analysis revealed that Immunoscore was superior to microsatellite instability in predicting patients' disease-specific recurrence and survival. These findings indicate that assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite-instability staging that could be an important guide for immunotherapy strategies.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…4,5,8,18,19 Gene expression profiling further linked Lynch syndrome with genes involved in antigen processing and presentation, T cell activation, natural killer cell-mediated cytotoxicity, and apoptosis. 8,20–22 Loss of B2M in 28% of the Lynch syndrome tumors was within previous reported range of 21–30% and are likely caused by frameshift mutations in microsatellite regions of the B2M gene (Figure 1). 13,15 The tumorigenic event of B2M loss is likely occurring in the middle of the adenoma-carcinoma sequence since B2M loss has not been found in metastasizing tumors or MMR deficient adenomas.…”

“…According to previous studies the number of lymphocytes infiltrating the cancer nest areas was counted at high magnification in an area corresponding to 0.135 mm. 6-8 The mean number of infiltrating lymphocytes in the TMA cores was used. For clinical statistics and correlation analyses the exact cell count was used.…”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…27 Indeed, MMR-deficient CRC tumors are characterized by denser CD8 + T cell infiltration. 30 They also have higher expression levels of inhibitory checkpoint molecules, probably to resist immune-mediated tumor elimination. 31 Together, enhanced immune cell infiltration and upregulation of inhibitory immune checkpoints may render MMR-deficient CRC more sensitive to PD-1/PD-L1 blockade than MMR-proficient CRC.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…In patients with stage II colorectal cancer who also had low immunoscores (high-risk), about 21% (375/1,808) had an estimated 5-year relapse-free survival (RFS) of 76.8%, whereas 26% of patients in the same demographic group with high immunoscores (low-risk) had a 5-year RFS of 91.2%. Immunoscores were also a better prognostic for survival in newly diagnosed patients with localized colorectal cancer (14) and were individually prognostic of DFS in FOLFOX-treated patients (15). Approximately 20% of MSS patients with high immunoscores were found in a small (unvalidated) cohort of patients (14).…”

“…Immunoscores were also a better prognostic for survival in newly diagnosed patients with localized colorectal cancer (14) and were individually prognostic of DFS in FOLFOX-treated patients (15). Approximately 20% of MSS patients with high immunoscores were found in a small (unvalidated) cohort of patients (14). The frequency of MSI-H status varied across different disease stages (stage II, 9%; stage III, 12%; and stage IV, 4%; ref.…”