1656P - Targeting NPC1L1 rescues anti-tumor immunity and improves immunotherapeutic efficacy in pancreatic cancer

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.