A. Ferrantella1, B. Giri1, S. Kurtom1, M. Tarique1, V. Sethi1, H. K. Jacob1, P. Sharma1, P. Roy1, S. Lavania1, A. Saluja1, V. Dudeja1 1University of Miami,Department Of Surgery,Miami, FL, USA
Introduction: Preclinical studies have demonstrated that an immune response can be generated against pancreatic cancer, but current immunotherapeutic strategies have not been successful at changing the course of the disease. Thus, there is need to evaluate novel strategies to elicit an anti-tumor response. In the current study, we evaluate the bacterial outer membrane product lipopolysaccharide (LPS) as a therapeutic agent to provoke an immune response against pancreatic cancer.
Methods: KPC pancreatic cancer cells (derived from the KrasG12D/+, Trp53R172H/+, Pdx-1-Cre model) were injected into the pancreata of C57BL/6 mice to induce tumors, and the orthotopic tumors were resected after 25 days. Following resection, the mice were randomized to receive LPS (5mg/kg) or vehicle twice weekly by intraperitoneal injection, and the mice were followed for cancer recurrence. In a separate experiment, KPC cancer cells were injected into the spleens of C57BL/6 and Rag1-knockout mice to induce liver metastases. Following intra-splenic injection, the mice were randomized to receive low-dose LPS (1mg/kg), high-dose LPS (5mg/kg), or vehicle twice weekly. Liver metastases were measured at the endpoint, and immunophenotyping was performed by flow cytometry. Finally, subcutaneous tumors were induced in C57BL/6 mice using MC38 colon cancer and Braf-Pten melanoma cell lines. After 15 days, the mice were randomized to receive either LPS or vehicle twice weekly, and the tumor volumes were serially measured.
Results: LPS treatment significantly reduced cancer recurrence following resection of pancreatic tumors, and the median survival for the LPS-treated mice was more than double that of the vehicle-treated mice. Both low-dose and high-dose LPS treatments drastically suppressed liver metastasis in C57BL/6 mice, but the effect of LPS was abrogated in the absence of an adaptive immune system in Rag1-knockout mice, which lack mature T and B cells. Intriguingly, we observed that, in addition to promoting the classically activated (M1) macrophage phenotype, there was a significant reduction in the pro-tumorigenic myeloid-derived suppressor cell (MDSC) populations, which are known to suppress T cell activity. LPS treatment decreased the growth of colon cancer and melanoma, suggesting that this strategy can be effective in other cancers as well.
Conclusion: Our findings demonstrate that LPS can stimulate the adaptive immune system to suppress the progression of pancreatic cancer. Elucidating the mechanism by which this anti-tumor response is triggered by LPS, and possibly even other pathogen-associated molecular patterns (PAMPs), could lead to identification of novel targets for activating the immune system against cancer, either alone or in combination with contemporary immunotherapeutic strategies.