A Nano-sized system sensatizing colorectal cancer to immunotherapy

Despite the recent progress in cancer immunotherapies, most patients do not benefit from the currently-available immune checkpoint blockers, and many develop severe immune-related adverse events. Therefore, it is urgent to develop alternative effective immunotherapeutic approaches. To this end, we synthesized a dendritic cell (DC)-targeted nano-based system to successfully modulate colorectal cancer (CRC) imune cell interactions to control tumor growth and improve overall survival. The failure of immunotherapies to yield clinical response in CRC is partially attributed to the inefficient antigen presentation by DC, which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). To overcome these hurdles, we set to design a novel Poly (lactic acid) (PLA) and Poly(lactic-co-glycol) (PLGA)-based nanoparticles (NP) that were prepared by a modified double emulsion (w/o/w) solvent evaporation method, using carbohydrate-grafted polymers to deliver combinations of CRC antigens and toll-like receptor ligands to DC. NP was fully characterized using Dynamic Light Scattering, Laser Doppler Electrophoresis, and Atomic Force Microscopy, to determine the mean average size, surface charge, and morphology, respectively. The amount of CRC antigens and immune potentiators entrapped within the NP were determined by fluorescamine and Oligreen ssDNA quantification kit, respectively. The biodistribution profile and DC accumulation were assessed in vivo and evaluated by flow cytometry. The anti-tumor immune-mediated effect was evaluated in vivo in CRC-bearing mouse models. Our NP presented an average diameter below 200 nm, narrow polydispersity index, slightly negative surface charge, spherical morphology, and high loading of the antigens and the immune potentiators. Cy5.5-labeled NP were extensively internalized by DC and triggered their activation in vivo, increasing the expression of DC-related co-stimulatory molecules such as CD80, CD86, and CD40. Furthermore, the immunotherapeutic effect of our nano-based platform revealed that the NP successfully induced a potent immune-mediated anti-tumor response, sensitizing the tumor microenvironment to anti-PD-1, ultimately leading to prolonged survival. The developed NP induced a strong antigen-specific immune response and overall sensitized CRC to the clinically-relevant anti-PD-1.