An immunogenic cell death-related signature predicts prognosis and immunotherapy response in stomach adenocarcinoma.

Abstract

The immunogenic cell death (ICD) is a specific type of regulatory cell death (RCD), which induces adaptive immunity against antigens of dead cells. ICDs have received increasing attention for their potential role in tumor microenvironment reprogramming and immunotherapy. However, the relationship between ICD-related features and stomach adenocarcinoma (STAD) prognosis, immune cell infiltration and immunotherapy remains unclear. Patients were divided into different ICD-related subtypes by consensus clustering. The differences in prognosis, Tumor microenvironment (TME), and immune checkpoint expression between different ICD-related subtypes were systematically assessed. Additionally, we constructed an ICD-related gene risk score (ICDRS). We systematically analyzed the correlation between ICDRS and prognosis, TME, immunotherapy response and drug sensitivity of gastric cancer. In addition, we explored the role of TGM2 in promoting gastric cancer progression through in vitro experiments. We identified three ICD-associated subtypes by consensus clustering. The ICD gene was highly expressed in Cluster B. Compared with the other two subtypes, Cluster B had better prognosis, higher immune response signaling activity, massive immune cell infiltration and lower tumor purity. Immune checkpoint (ICP) and human leukocyte antigen (HLA) related genes were also highly expressed in Cluster B. In addition, we found that ICDRS is an effective indicator for predicting the prognosis and immune efficacy of STAD. The low ICDRS group has the characteristics of good prognosis, high tumor mutation burden (TMB), high microsatellite instability (MSI), and sensitivity to immunotherapy, while the high ICDRS group is prone to immune escape and immunotherapy resistance. In addition, we found that down-regulating TGM2 gene can inhibit the proliferation and migration of gastric cancer cells through in vitro experiments. Our study found that the model based on ICD features is helpful to clarify the TME characteristics of STAD, and has important clinical significance for evaluating the prognosis and immunotherapy response of STAD patients. TGM2 plays an important role in the progression of STAD, suggesting that TGM2 can be used as a new target for the treatment of STAD.