Multi-omics reveals the immunological features and the immune checkpoint blockade potential of colorectal medullary carcinoma

Abstract Purpose: Colorectal medullary carcinoma (MeC) is extensive lymphocyte infiltration and is associated with an active immune response. However, studies to comprehensively explore the immune landscape and efficacy of immune checkpoint blockade (ICB) therapy in MeC are limited. Experimental Design: We screened 47 cases of MeC from the Harbin Medical University Cancer Hospital cohort. The immunologic characteristics of MeC were analyzed by targeted exon sequencing, NanoString nCounter gene expression sequencing, IHC, multiplexed immunofluorescence, and T-cell antigen receptor sequencing. An additional 47 patients with MeC who received ICB therapy were included in the retrospective analysis to verify the efficacy of immunotherapy. Results: Genomically, MeC tends to have a higher proportion of mismatch repair protein deficiency/microsatellite instability (MSI), ARID1A mutation, and ASCL2 amplification. Gene expression shows enriched immune response–related pathways while downregulating oncogenic pathways, such as glycolysis, epithelial–mesenchymal transition, and Wnt/β-catenin signaling. Further immune characterization showed that MeC showed advantages in antigen presentation, co-stimulatory molecules, effector molecules, immune checkpoints, and immune cell abundance. More importantly, both MSI and microsatellite-stable type MeC showed a similar state of high infiltration of immune cells, even better than MSI non-MeC. MeC infiltrated massive highly clonal immune cells, especially intraepithelial CD8+ T cells. In the retrospective cohort, there were 30 patients with MeC who received ICB therapy and achieved complete or partial response with an objective response rate of 63.8%, especially including 16 patients with microsatellite-stable colorectal cancer. Conclusions: MeC is a pathologic subtype with an active immune response and is a promising group for ICB therapy. This heightened immune response was not limited to the patients' microsatellite status.