Abstract 1656P
Background
The dysfunction of anti-tumor immunity of pancreatic adenocarcinoma (PAAD) is critically attributable to the failure of multi-therapies. Cholesterol is an essential component of mammalian cell membranes essential to the proliferation and TCR activation of CD8+T cells, and it has been revealed that cholesterol metabolism plays an important role in sustaining the antitumor activity of CD8+T cells. Although the cholesterol metabolism reprogramming has been implicated in carcinogenesis, including PAAD, how tumors reprogram cholesterol metabolism to sustain their survival and suppress anti-tumor immunity remains largely unknown.
Methods
RNA-seq, CyTOF, CD8+ T cell isolation and cultivation, flow cytometry analysis etc. biological experimental techniques.
Results
PAAD cells ectopically express NPC1L1 to suppress the activation and proliferation of antitumor CD8+ T cells in tumor microenvironment. NPC1L1 overexpression promotes PAAD cells to evade the immunosurveillance of CD8+T cells and is responsible for PAAD development and progression. And pancreatic npc1l1-silencing KPC mice led to a marked decrease in late-stage intraepithelial neoplasia lesions and malignant tumor formation. Our findings demonstrated that PAAD cell-expressed NPC1L1 functions as a checkpoint molecule to suppress the cytotoxicity of antitumor CD8+T cell via NPC1L1-ITGAL interaction. Moreover, NPC1L1-ITGAL interaction promotes the efflux of intracellular cholesterol from antitumor CD8+ T cells, consequently leading to a suppression of TCR activation and proliferation of antitumor CD8+ T cells. The NPC1L1 inhibitor ezetimibe promotes the antitumor response mediated by CD8+ T cells and synergizes with PD-1 blockade to enhance its therapeutic efficacy in PAAD.
Conclusions
Ectopically overexpressed NPC1L1 on cell membrane as a metabolic-immunologic two-pronged checkpoint is an ingenious trick of pancreatic cancer cells to gain at the expense of CD8+ T cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China; National Postdoctoral Program for Innovative Talent; ScienceFoundation of Chongqing; Hospital Managed Fund Projects.
Disclosure
All authors have declared no conflicts of interest.
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