Priority Areas in the Laboratory:
Immunosuppression in the pancreatic tumor microenvironment. Our primary research efforts have explored the mechanisms through which the tumor microenvironment promotes tumor growth and immunosuppression. These translational studies discovered that factors secreted by stromal cells derived from pancreatic cancer patients, such as IL-6, can promote the differentiation of immunosuppressive populations in a STAT3 dependent mechanism. Additionally, recent pre-clinical studies provide evidence that blocking IL-6 can enhance the efficacy of checkpoint blockade immunotherapy. These studies have provided the rationale for examining other inflammatory factors from the tumor microenvironment as potential therapeutic options in the setting of pancreatic cancer and other GI maligniancies. The laboratory is investigating how cell surface proteins (e.g. CD200) expressed by the tumor and stromal cells promotes the expansion and function of immunosuppressive cell types like MDSC.
Use of natural productions to modulate immunity during chronic inflammation and carcinogenesis. It is well recognized that chronic inflammation plays a major role in carcinogenesis. This concept strongly implies that dysregulated immunity occurs at even the earliest stages of tumor development. We feel that neutralizing aberrant inflammatory responses may in fact be a viable first line of defense against cancer. One very interesting approach to limiting inflammation lies in use of dietary intervention with foods possessing known chemopreventive activity. Our research has shown that active metabolites from dietary compounds such as soy, black raspberries, and tomatoes can alter inflammatory factors and immune populations. Our preliminary work has led to an USDA-AFRI foundation grant (Co-PI: GRT00048283) on a soy-tomato enriched diet as modulator of inflammation in men with obesity.
Exploring how cancer induced cachexia affects immune suppression and immunotherapy efficacy. Cancer cachexia is a complex catabolic syndrome involving tumor- and host-derived signaling resulting in metabolic derangement that ultimately leads to involuntary weight loss and muscle protein degradation. Cachexia is broadly associated with poor outcomes from diverse anti-cancer therapies. In particular cachexia has been associated with poor outcomes from ICI therapies. Cancer cachexia is prevalent and a large issue for patients with solid tumor malignancies such as lung and pancreatic cancer.Antibody catabolism occurs through endocytosis and pinocytosis, in which antibodies are trafficked into lysosomes and degraded. Both therapeutic and endogenous IgG antibodies are salvaged from lysosomal degradation in sorting endosomes by binding to the neonatal Fc receptor (FcRn, FCGRT) under acidic conditions which facilitates their recycling back into circulation. Our laboratory has an active interest in understanding how cachexia affects immunotherapy antibody clearance and efficacy in cancer patients
