Targeting Tumor immune microenvironment in GI Cancers 4277

Abstract Description KRAS mutation on codon-12 is present in 70–95% of Pancreatic Ductal Adenocarcinoma (PDAC) cases and it drives PDAC growth and progression. Galectin-1 (Gal-1) is present in both PDAC and stromal cells, being involved in tumor microenvironment, immune cell activation and metastasis. Therefore, this study discusses the efficiency of combined inhibition of mutated KRASG12D and Gal-1 inhibition to effectively suppress PDAC growth and progression. For this we have delivered KRASG12D inhibiting siRNA (siKRASG12D) using a superparamagnetic iron oxide nanoparticle (SPION) and a galectin inhibitor. Our results demonstrate that combined targeting of siKRAS and Gal-1 inhibited PDAC cells and tumor spheroids. Combination treatment inhibited the fibrotic tumor growth and increased survival rate in KrasG12D;LSL-Trp53R172H syngeneic mouse model of PDAC. It increased infiltration of total T cell population and CD8+T cells, reduced the population of myeloid-derived suppressor cells (MDSCs) by 50% (CD45+, CD3-, CD11b+, Ly6C high, Ly6G-) and T-Regulatory cells (Treg) by 57% (FoxP3+CD25+CD45+CD3+) and increased memory T cells by 34% in mice. This therapy targeting KRAS G12D mutation with a Gal-1 inhibition has a potential to modulate the oncogenic network and tumor immune microenvironment and can lead to a novel sustainable therapeutic approach to target PDAC growth and improve patient survivability. Funding Sources CPRIT TREC Award RP230419 Herb Kosten foundation for pancreatic cancer research UTRGV startup to Dr. Khan Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)