A Nano-sized system sensitizing colorectal cancer to immunotherapy

Despite the recent progress in cancer immunotherapies for colorectal cancer (CRC), the third leading cause of cancer-related deaths in the United States, most patients do not benefit from the current approved immune checkpoint blockers (e.g., anti-PD-1), and develop severe immune-related adverse events. Therefore, there is an unmet need to seek for alternative effective immunotherapeutic approaches. Dendritic cells (DC) have an important role in the induction and regulation of the cellular and humoral arms of the immune system. In CRC, even though tumor-infiltrating T cells express tumor-associated antigens (TAA), inefficient antigen presentation by DC results in insufficient T cells stimulation. To overcome these hurdles, we set to design a novel polymeric-based nanoparticle (NP) for the delivery of CRC antigens, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), and toll-like receptor ligands to DC. Our synthesized NP demonstrate an average diameter below 200 nm, a narrow polydispersity index, a slightly negative surface charge, and a spherical morphology. Our system entrapped high loadings of the CRC antigens (~80%) and the immune potentiators (~90%). Biodistribution profile has proved that fluorescently (Cy5)-labeled NP were extensively internalized by DC. In addition, the evaluation of mature DC-related co-stimulatory molecules such as CD80, CD86, and CD40 showed that NP triggered DC activation in-vivo. Finally, 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, and ultimately leading to prolonged survival, in anti-PD-1 clinically-resistant CRC.