HCST Expression Distinguishes Immune-hot and Immune-cold Subtypes in Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent malignancy of the pancreas, and the incidence of this disease is approximately equivalent to the mortality rate. Immunotherapy has made a remarkable breakthrough in numerous cancers, while its efficacy in PDAC remains limited due to the immunosuppressive microenvironment. Immunotherapy efficacy is highly correlated with the abundance of immune cells, particularly cytotoxic T cells. Therefore, molecular classifier is needed to identify relatively hot tumors that may benefit from immunotherapy. Methods: In this study, we carried out a transcriptome analysis of 145 pancreatic tumors to define the underlying immune regulatory mechanism driving the PDAC immunosuppressive microenvironment. The immune subtype was identified by consensus clustering, and the underlying PDAC immune activation mechanism was thoroughly examined using single sample gene set enrichment analysis (ssGSEA). Area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to assess the accuracy of the molecular classifier in differentiating immunological subgroups of PDAC.5 Results: The protein level of molecular classifier was verified by immunohistochemistry in human PDAC tissue. Immune-hot tumors displayed higher levels of immune cell infiltration and immune checkpoint, in line with enriched immune escape pathways. Hematopoietic cell signal transducer (HCST), a molecular classifier used to differentiate immunological subtypes of PDAC, has shown a substantial link with the expression levels of cytotoxic markers, such as CD8A and CD8B. At the single cell level, we found that HCST was predominantly expressed in CD8T cells. By immunohistochemistry and survival analysis, we further demonstrated the prognostic value of HCST in PDAC. Conclusion: We identified HCST as a molecular classifier to distinguish PDAC immune subtypes, which may be useful for early diagnosis and targeted therapy of PDAC.