182P - Innovative nano-immunotherapy for modulating tumor-immune interactions and microbiome in pancreatic cancer

Background

Large desmoplasia, unique tumor microbiome and the immunosuppressive tumor microenvironment has been observed in pancreatic ductal adenocarcinoma (PDAC). Branched polypeptides (BP) are complex engineered structures acting as immunomodulators to control tumor growth. Immune checkpoint inhibitors (ICI) induce antitumor responses, while inhibition of focal adhesion kinase (FAK) reduces fibrosis and boosts immune surveillance. This study aimed to evaluate the in vivo antitumor immune effects and microbiota diversity induced by BP conjugated with PDAC-associated peptide antigens MHCI/II ([BP-MHCI/II]) in combination with an ICI and a FAK inhibitor (FAKi).

Methods

BP were conjugated with MHCI and MHCII-PDAC peptides. To assess the impact of the nanoconjugate on orthotopic PDAC tumor growth, KPC cells were implanted in the pancreas of mice. On day 7, mice were immunized with two doses of either PBS, free antigens/adjuvants (MHCI/MHCII antigens + Toll-like receptor ligands), or [BP-MHCI/II] mixed with adjuvants and combined with ICI and FAKi. Mice weight was monitored regularly. On day 20, PDAC tumors were collected. Functional markers of tumor-infiltrating immune cells were quantified by FACS, and gut and tumor-associated microbiota diversity was analyzed through 16S metagenomic sequencing, followed by QIIME2.11 bioinformatic tools.

Results

[BP-MHCI/II] exhibited a mean diameter of 40 nm and a zeta potential (ZP) of -25 mV, with MHCI and MHCII peptide loading efficiencies of 20% and 13%, respectively. Tumor reduction was more pronounced in mice treated with [BP-MHCI/II] in combination with ICI and FAKi, compared to PBS. The combination treatment modulated tumor-infiltrating immune cells promoting antitumor immunity. Also, gut and tumor microbiota composition and diversity varied among treatments.

Conclusions

The combination of [BP-MHCI/II] with ICI and FAKi represents a promising strategy to overcome tumor growth, to modulate immune cells in tumor microenvironment and microbiota composition in PDAC.

Legal entity responsible for the study

The author.

Funding

Fundação para a Ciência e Tecnologia (FCT).

Disclosure

The author has declared no conflicts of interest.