Pancreatic cancer is one of the lethal types of cancer due to its ability to metastasize throughout the body. Despite recent advances in pancreatic cancer research, all the current cancer therapies have severe limitations in treating metastatic pancreatic cancer. Therefore, there is a need for a treatment regimen that can both break the immunosuppressive nature of the tumor and control cancer metastasis. We used a novel localized ablative immunotherapy, a combination of interstitial photothermal therapy (iPTT) and intratumoral administration of immunostimulant, to treat pancreatic tumors in mouse model. Here, we investigated the effects of iPTT on the tumor microenvironment or orthotopic mouse model to determine the optimal ablative effects. This treatment regimen will later be combined with an immunostimulant for a synergistic approach to provide an effective treatment modality for metastatic pancreatic cancers.
Localized ablative immunotherapy (LAIT) combines targeted photothermal therapy (PTT) and immunotherapy to ablate the primary tumor site using laser irradiation while inducing systemic and specific anti-tumor immune responses for the treatment of metastatic cancers. The therapeutic efficiency of LAIT synergized with nanomedicine has been proven to be safe and effective for cancer treatment. Here, graphene oxide (GO) is used as a light-absorbing agent to enhance the generation of heat caused by PTT and increase its tumoricidal effect. GO is also a nanocarrier for drug delivery of the immune-stimulating biopolymer N-dihydrogalactochitosan (GC). GC is an innovative and effective immunostimulant/adjuvant with surfactant properties that was used to functionalize GO nanosheets. This work was designed to determine the main properties of GO/GC nanoparticles (NPs) when used in combination with PTT. The therapeutic efficacy of the treatment is being assessed on a highly aggressive and poorly immunogenic pancreatic tumor model in mice. Overall, GO/GC shows promising properties as a stable, safe, and effective photothermal agent and immunostimulant for nano-ablative immunotherapy for cancer.
A novel biopolymer, N-dihydrogalactochitosan (GC), is developed for inducing immune responses. GC stimulates innate and adaptive antitumor and antiviral immunities. In this study, we investigated the mechanism of GC-induced immune responses through in vitro and in vivo studies. We find that GC drives type I IFN production and IFN responses in antigen presenting cells (APCs). Furthermore, GC drives alternative activation of STING leading to inflammatory cell death that enhances dendritic cell (DC) activation. In vivo, GC induced a potent response of type I IFN and upregulated genes associated with STING signaling within the tumor microenvironment (TME). Because of its potent immunological stimulation ability and its unique mechanism in inducing the immune responses, GC has been used in combination with laser photothermal (PTT) for the treatment of cancers. We find that PTT+GC induced specific modulation of immune cells, positively corresponding to long-term survival of cancer patient.
Pancreatic cancer is one of the deadliest types of cancer due to its ability to metastasize throughout the body. According to the Surveillance, Epidemiology, and End Results Program (SEER), the overall 5-year relative survival rate for pancreatic cancer is 10.8% but once the cancer metastasizes, this survival rate reduces to 3%. Despite recent advances in cancer research, all the current cancer therapies have severe limitations in treating pancreatic cancer. One major challenge in pancreatic cancer research is the lack of an accurate model of the pancreatic tumor and its microenvironment. The common two-dimensional (2D) models are ineffective in mimicking solid tumors. Therefore, there is a need for a better in vitro model to accurately mimic the characteristics of solid pancreatic tumor and to improve assessments for cancer therapies. Here, we generated multicellular tumor spheroids from an aggressive pancreatic cancer cell line, Panc02-H7, and monitored its growth. We also investigated the effects of photothermal therapy through irradiation of a near-infrared laser, which is used to induce immunogenic cell death (ICD) on the tumor spheroids. This three-dimensional (3D) tumor model mimics pancreatic tumors in vitro and this study can generate translatable results and, consequently, guide clinical studies.
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