Abstract
Abstract Introduction: Pancreatic cancer is a major cause of cancer-related mortality with a dismally low overall survival. Despite advancement in the cancer immunotherapy, pancreatic cancer remains unresponsive due to its immunosuppressives. We have established that lipopolysaccharide (LPS) reduces tumor burden in pancreatic cancer mouse-models by stimulating anti-tumor immunity and infiltrating cytotoxic CD4+ T-cells in the tumor-microenvironment. Here, we are investigating how LPS immuno-modulates pancreatic cancer niche and brings anti-cancerous effect. Methods: Pancreatic cancer-cells (KPCs) were implanted in C57BL/6, TRIF KO, MyD88 KO and TLR4 flox/flox LysmCre (TLR4f/f) mice subcutaneously and were treated with LPS (1mg/kg) weekly. The animals were sacrificed at endpoints and tumors were evaluated. Subcutaneous KPC-LPS model in BL/6 mice were also coupled with clodronate treatment to deplete cells of myeloid lineage. Tumor samples were analyzed using flow-cytometry and RT- PCR for immunocyte infiltration and expression of immune-associated genes. Dendritic cells (DCs) were isolated from BL/6 and TLR4f/f mice, pulsed with KPC cancer cell antigen, treated with LPS and taken to flow cytometry. Such DCs were also co-cultured with CD4+ T-cells, which were then subjected to cytotoxicity against cancer cells Results: LPS therapy in wild-type pancreatic cancer mouse-model significantly reduced the tumor burden by stimulating anti- tumor immunity in tumor-microenvironment and caused significant upregulation of activated DCs and macrophages. The tumor regressing effect of LPS disappeared in absence of TRIF as well as MyD88 receptors in TRIF KO and MyD88 KO mice respectively. Macrophage depletion by clodronate attenuated influence of LPS on tumor burden, which again proved futile in TLR4f/f model. On antigenic stimulation and LPS treatment, DCs from BL/6 mice expressed higher frequency of co-stimulatory molecules such as CD40, CD80 and CD86 whereas TLR4f/f mice derived DCs did not show such a trend. When such BL/6 DCs were co-cultured with CD4+ T- cells, they expressed higher cytotoxicity against cancer cells. Conclusions: LPS treatment reduces tumor burden in pancreatic cancer model by stimulating anti-tumor immunity in tumor- microenvironment wherein cells of the myeloid lineage are indispensable. This anti-cancer effect executed by CD4+ T-cells in an MHC II dependent manner, seems to be mediated through dendritic cells. Designer TLR4-agonists have the potential to emerges as a novel immunotherapeutic agent and could be combined with available immune-checkpoint blockade therapies. Citation Format: Utpreksha Vaish, Tejeshwar Jain, Dhanisha S Suresh, Maria F Salcedo-Noriega, Srikanth Iyer, Troy Randall, Vikas Dudeja. Lipopolysaccharide (LPS) mediated Toll like receptor-4 (TLR4) agonism immuno-modulates pancreatic cancer niche via CD4T cells-Myeloid cells axis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B048.
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