Immunotherapy has demonstrated efficacy in colorectal cancer (CRC), primarily benefiting the microsatellite instability-high (MSI-H) population, which comprises approximately 15% of cases. However, it remains unclear whether any patients with microsatellite stability (MSS) CRC will benefit from immunotherapy. This study aims to identify a novel subtype within MSS CRC that may respond to immunotherapy. Single-cell RNA-sequencing data were utilized to define immune cell signatures in MSS CRC. Using these signatures, we developed a classification panel by integrating data from five independent transcriptomic databases. Spatial transcriptomics was employed to analyze gene panel localization. Multiple immunofluorescence assays were conducted to explore the tumor microenvironment. Additionally, organoids co-cultured with paired peripheral blood mononuclear cells were used to assess immunotherapy responsiveness. Signatures of multiple immune cell types were identified from the single-cell RNA-sequencing database for MSS CRC. Based on these signatures, MSS CRC was classified into two distinct subtypes: "immune-enriched" and "immune-desert", each exhibiting unique prognostic and tumor microenvironment profiles. The classification panel achieved an area under the curve greater than 0.9 across five independent databases. In a cohort of 223 patients, survival analysis indicated that "immune-enriched" patients had a significantly better prognosis. Multiple immunofluorescence assays revealed higher immune cell infiltration in these patients. When treated with anti-PD-1 antibodies, "immune-enriched" organoids in peripheral blood mononuclear cell co-culture models showed increased sensitivity. In conclusion, we have developed a panel that identifies a novel MSS CRC subtype with a tumor microenvironment resembling that of MSI-H CRC patients, demonstrating potential responsiveness to immunotherapy.
Xu et al. (Wed,) studied this question.