Identification and characterization of CLEC11A and its derived immune signature in gastric cancer.

Introduction: C-type lectin domain family 11 member A (CLEC11A) was characterized as a growth factor that mainly regulates hematopoietic function and differentiation of bone cells. However, the involvement of CLEC11A in gastric cancer (GC) is not well understood. Methods: Transcriptomic data and clinical information pertaining to GC were obtained and analyzed from publicly available databases. The relationships between CLEC11A and prognoses, genetic alterations, tumor microenvironment (TME), and therapeutic responses in GC patients were analyzed by bioinformatics methods. A CLEC11A-derived immune signature was developed and validated, and its mutational landscapes, immunological characteristics as well as drug sensitivities were explored. A nomogram was established by combining CLEC11A-derived immune signature and clinical factors. The expression and carcinogenic effects of CLEC11A in GC were verified by qRT-PCR, cell migration, invasion, cell cycle analysis, and in vivo model analysis. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and T cells in tumor samples extracted from mice were analyzed utilizing flow cytometry analysis. Results: CLEC11A was over-expressed in GC, and the elevated CLEC11A expression indicated an unfavorable prognosis in GC patients. CLEC11A was involved in genomic alterations and associated with the TME in GC. Moreover, elevated CLEC11A was found to reduce the benefit of immunotherapy according to immunophenoscore (IPS) and the tumor immune dysfunction, exclusion (TIDE). After validation, the CLEC11A-derived immune signature demonstrated a consistent ability to predict the survival outcomes in GC patients. A nomogram that quantifies survival probability was constructed to improve the accuracy of prognosis prediction in GC patients. Using shRNA to suppress the expression of CLEC11A led to significant inhibitions of cell cycle progression, migration, and invasion, as well as a marked reduction of in vivo tumor growth. Moreover, the flow cytometry assay showed that the knock-down of CLEC11A increased the infiltration of cytotoxic CD8+ T cells and helper CD4+ T into tumors while decreasing the percentage of M2 macrophages, MDSCs, and Tregs. Conclusion: Collectively, our findings revealed that CLEC11A could be a prognostic and immunological biomarker in GC, and CLEC11A-derived immune signature might serve as a new option for clinicians to predict outcomes and formulate personalized treatment plans for GC patients.

Immune checkpoint inhibitors and cellular immunotherapy for advanced gastric, gastroesophageal cancer: a long pathway.

Although the incidence rate and mortality of gastric/gastroesophageal cancer (G/GEJC) are declining globally, G/GEJC remains a health issue in East Asia. When diagnosed as advanced stage, treatment after serial lines of chemotherapy is limited, with a median overall survival of less than 1 year. Immunotherapy, including immune checkpoint inhibitors (ICIs) and cellular immunotherapy, has changed the prospects of cancer therapy by reversing immune suppression in the tumor microenvironment. As part of this review, we enumerated the clinical uses of ICIs related to the immunosuppressive signaling axis PD-1/PD-L1 and CTLA-4/B7. ICIs were initially approved as a secondary treatment option for patients with severe pretreating advanced gastric and gastroesophageal cancer (AG/GEJC). Till now, it has become the mainstream therapy in combination with chemotherapy and targeted therapy for patients identified by biomarkers. Numerous evidence showed microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden (TMB) and Epstein-Barr virus (EBV) status might be indicative to the use of ICIs. In addition, we discussed the current limitations and prospects of ICIs in AG/GGEJC, as well as the first clinical application of novel CAR-T cell therapies.