Tissue engineered cancer metastases as cancer vaccine to improve cancer immunotherapy.

Radiotherapy is often used to improve cancer immunotherapy outcomes. While there are both pre-clinical and clinical data supporting this approach, there are also significant challenges. One key challenge is that not all patients have tumors that can be easily treated with radiotherapy due to potential normal tissue toxicity and prior treatment. In addition, it is difficult to control the tumor microenvironment to promote the immune response after radiosurgery. To overcome these challenges, we hypothesize that we can engineer cancer metastasis and utilize irradiated engineered tumor cells as a personalized cancer vaccine to improve cancer immunotherapy. Herein, we report the development of engineered lung metastasis using decellularized rat lung tissue. Using the B16F10 melanoma tumor model, we showed that radiotherapy-treated engineered metastases are highly effective in improving cancer immunotherapy responses and more effective than in vivo metastasis. Our work has demonstrated the potential of applying tissue engineering to cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Combination of radiation and immunotherapy are an effective way to treat metastasis. Despite their success, long term response still remains low. Tumor microenvironment evading the immune response, normal tissue toxicity to radiation and inaccessibility to radiosurgery are some of the limitations. To overcome these challenges, in this paper we present with data supporting the use of high dose radiation treated ex vivo engineered B16F10 metastasis model using decellularized lung scaffolds. These engineered metastases closely mimic the in vivo tumors and when given into tumor bearing mice along with check point inhibitors are highly effective in improving the cancer immunotherapy response.

Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis.

Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA. SIGNIFICANCE: Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.

The role of liver microenvironment in hepatic metastasis.

Metastasis is still poorly understood and thus further research must be conducted to provide insight into the driving factors. Novel research has revealed the significance of the microenvironment in the delegation of metastasis, expanding the field of cancer metastasis to cells and cell environments surrounding the migrated tumor cells. Research on hepatic metastasis is an ever-growing domain of this field, as several primary tumors can metastasize to the liver. The two features within the liver that promote metastasis-cellular and acellular-are found in the current interpretation of liver microenvironment. Novel findings of both are included in this review. Different hypotheses detailing the methods by which metastasis can occur must be included to understand the significance of the microenvironment, as well as a brief overview of the methods that can be used during research. This review aims to highlight the importance of liver microenvironment on the development or potential regression of hepatic metastasis through discussing both acellular and cellular components of liver microenvironment and their interaction with metastasis.