Akbay Lab

Amino acid metabolism is recognized as a critical immune regulatory control point, which tempers T cell response. Tryptophan degradation limits innate and adaptive immune responses by depleting the tumor local microenvironment of tryptophan and by promoting the accumulation of kynurenine resulting from the catabolism of tryptophan. Similar to tryptophan metabolism, arginine degradation contributes to T cell suppression. While most cells can synthesize arginine from citrulline, T cells are dependent on extracellular arginine. Arginases and NOS are the main enzymes regulating extracellular arginine levels in the tissues. Though the exact role of activation of arginase across the different genomic subtypes of lung cancer is not fully understood, we showed that targeting arginase is an effective therapeutic strategy in Kras mutant lung cancers (Miret et al, JITC).

Alterations in other metabolites such as Adenosine have also been implicated in immune suppression. We showed that EFGR mutations activate the Adenosine pathway and suppress anti-tumor immunity through the accumulation of adenosine in the tumor tissue and increased uptake by the T cells. Our current projects are focused on understanding the role of these altered metabolic pathways in immune resistance in genomically classified tumors using transgenic, syngeneic, and humanized cancer models.