Researchers Identify Immune Subtypes of EC, Highlighting Diversity of the Immune Microenvironment

The researchers identified 3 immune subtypes of esophageal cancer (EC) among the samples, all of which had different prognostic implications.

Researchers say they have identified immune subtypes (ISs) specific to esophageal cancer (EC) that offer insight into the complex nature of the immune microenvironment.

Based on their findings, the group highlighted the importance of extensively assessing ISs from EC samples to understand the personalized nature of the tumor immune microenvironment (TIME). This, they say, can eventually lead to more personalized treatment for patients with the disease.

Their findings recently appeared in Annals of Medicine.

“Considering the complex immune function, a more in-depth description of the overall characteristics of the TIME will help improve the level of individualized precision treatment,” wrote the researchers, who found that the distribution of ISs in functional modules is different.

They added, “We reported for the first time that there is significant intra-class heterogeneity in ISs of EC, conferring different prognostic outcomes. Taken together, these findings alert the insufficiency of therapeutic efficacy and prognosis prediction based on a single immune index.”

The researchers identified 3 ISs among the samples, all of which had different prognostic implications; IS3 subtypes carried a favorable prognosis while IS1 subtypes carried a worse prognosis. They also analyzed the association of tumor mutational burden (TMB)—a supported predictive biomarker of immunotherapy—among the 3 subtypes, finding that TMB in IS1 was significantly higher than in IS2 and IS3.

Data from 2 cohorts were leveraged for analysis:

  • 161 samples with RNA sequencing of Cancer Genome Atlas esophageal carcinoma clinical entries (the TCGA-ESCA cohort) from the TCGA Genomic Data Commons portal
  • 119 samples of GSE53624 microarray data with survival information from the Gene Expression Omnibus

The researchers also identified key genes in the immune microenvironment of EC—BHLHE22, MXRA8, SLIT2 and SPON1, all of which were associated with EC prognosis. Based on the gene signature, the researchers created a risk score model they say can be used for prognosis prediction: −0.16514291×BHLHE22−0.03964046×MXRA8−0.15242778×SLIT2−0.05553572×SPON1.

The risk score, they say, can be used to stratify high-risk and low-risk patients from the TCGA-ESCA cohort and has been independently validated in the GSE53624 cohort.

“Interestingly, SLIT2 expression is downregulated in EC, associating with poor prognosis,” noted the researchers. “A previous study showed that miR-1179 promotes cell invasion of [esophageal squamous cell carcinoma] through the SLIT2/ROBO1 axis. In other cancer types, SPON1 promotes the metastasis of human osteosarcoma, while methylated BHLHE22/CDO1/CELF4 panel could be used for endometrial cancer screening. The association of these genes in EC worth further validation by basic and clinical studies.”


Xie Y, Shi X, Chen Y, et al. The intra-class heterogeneity of immunophenotyping and immune landscape in oesophageal cancer and clinical implications. Ann Med. 2021;53(1):626-638.