Tumor escape from immune recognition is an emerging hallmark of cancer that can significantly compromise the efficacy of current immunotherapeutic strategies. Immune suppressive mechanisms within tumor-draining lymph nodes and the tumor microenvironment contribute to the ability of tumor cells to escape anti-tumor immunity.
In order to study the role of escape mechanisms within the tumor microenvironment, the laboratory of Edwin R. Manuel, Ph.D., has developed a versatile, Salmonella typhimurium (ST)-based platform that utilizes shRNA plasmid technology to target expression of proteins known to contribute to immune suppression.
One such protein, indoleamine 2,3-dioxygenase (IDO), is overexpressed in a variety of malignancies and has been shown to induce maturation of regulatory T cells and suppress tumor-reactive immune cells by virtue of its ability to deplete the essential amino acid tryptophan. Administration of ST targeting IDO (shIDO-ST) resulted in significant tumor-specific IDO-silencing and regression in preclinical models of melanoma and pancreatic cancer, which was dependent on activation of tumoricidal neutrophils. "Our group is currently using the shRNA-ST platform to target oncogenes involved in “oncogene addiction”, such as mutant KRAS in pancreatic cancer" states Dr. Manuel.
Another focus of Dr. Manuel’s research includes the use of checkpoint inhibitors to improve efficacy of cancer immunotherapies, specifically, therapeutic vaccines encoding for tumor antigens such as survivin and Wilms' tumor antigen 1 (WT1). "The overall objective of our research program will be to continue to generate novel approaches that overcome tumor escape to elicit potent anti-cancer immune responses, which can then be translated to the clinic for the treatment of aggressive cancers."