Mechanisms of HIF1A-mediated immune evasion in gastric cancer and the impact on therapy resistance

Background: The high prevalence and detrimental effects on patient outcomes make gastric Cancer (GC) a significant health issue that persists internationally. Existing treatment modalities exhibit limited efficacy, prompting the exploration of Immune Checkpoint inhibitors as a novel therapeutic approach. However, resistance to immunotherapy poses a significant challenge in GC management, necessitating a profound grasp of the intrinsic molecular pathways.

Methods: This study focuses on investigating the immunosuppressive mechanisms of quiescent Cancer cells (QCCs) in GC, particularly their resistance to T-cell-mediated immune responses. Utilizing mouse models, gene editing techniques, and transcriptome Sequencing, we aim to elucidate the interactions between QCCs, immune cells, and key regulatory factors like HIF1A. Functional enrichment analysis will further underscore the role of glycolysis-related genes in mediating immunosuppression by QCCs.

Results: The Cancer cells that survived GC treated with T-cell therapy lost their proliferative ability. QCCs, as the main resistance force to immunotherapy, exhibit stronger resistance to CD8⁺ T-cell attack and possess higher cancer-initiating potential. Single-cell Sequencing analysis revealed that the microenvironment in the QCCs region harbors more M2-type tumor-associated macrophages and fewer T cells. This microenvironment in the QCCs region leads to the downregulation of T-cell immune activation and alters macrophage metabolic function. Transcriptome Sequencing of QCCs identified upregulated genes related to chemo-resistance, hypoxia, and glycolysis. In vitro cell experiments illustrated that HIF1A promotes the transcription of glycolysis-related genes, and silencing HIF1A in QCCs enhances T-cell proliferation and activation in co-culture systems, induces Apoptosis in QCCs, and increases QCCs' sensitivity to Immune Checkpoint inhibitors. In vivo, animal experiments showed that silencing HIF1A in QCCs can inhibit GC growth and metastasis.

Conclusion: Unraveling the molecular mechanisms by which QCCs resist T-cell-mediated immune responses through immunosuppression holds promising implications for refining treatment strategies and enhancing patient outcomes in GC. By delineating these intricate interactions, this study contributes crucial insights into precision medicine and improved therapeutic outcomes in GC management.

Drug resistance; Gastric cancer; Glycolysis; HIF1A; Immune-suppressive microenvironment; Quiescent cancer cells; Single-cell sequencing; T cells.