Fig. 4

Schematic representation of the postulated biology of the three distinct NSCLC phenotypes, as emerged by the immunohistochemical findings. a Arginine synthesis proficient tumors expressing ASS1, with tumor stroma that does not consume arginine (ARG2 deficient). These tumors synthesize arginine for their own demands and release excess arginine to the stroma, fertilizing this to the thriving of infiltrating TILs that use arginine for their activity and proliferation. Arginine can also be used by TILs for the release of NO through arginine metabolism by iNOS enzymatic activity. As immune surveillance prevails, these tumors have a favorable prognosis. Targeting these tumors with ASS1-inhibitors may be of value provided that this will not damage the anti-tumor immune balance. b ASS1 expression by cancer cells in parallel with ARG2 expression by stroma CAFs predict for the depletion of the released arginine in the stroma. The low availability of arginine blocks the proliferation and activation of TILs, contributing to a cold immune environment. This is linked with a poor prognosis. Targeting these tumors with ARG-inhibitors may restore immune surveillance by fertilizing the tumor stroma for TIL thriving. c Auxotrophic tumors lacking ASS1 depend on exogenous arginine availability that can also be further suppressed by ARG2 expression by CAFs. These lung tumors are immunologically cold and are associated with a poor prognosis. Arginine-deprivation therapies (arginase, arginine deiminase administration) may eliminate the already low tumor arginine content, promoting cancer cell arginine starvation and death