Rho GTPase effectors and NAD metabolism in cancer immune suppression

Abstract

Sustained proliferative signaling and de-regulated cellular bioenergetics are two of the chief hallmarks of cancer. Alterations in the Ras pathway and its downstream effectors are among the major drivers for uncontrolled cell growth in many cancers. The GTPases are one of the signaling molecules that activate crucial signal transducing pathways downstream of Ras through several effector proteins. The GTPases (GTP bound) interact with several effectors and modulate a number of different biological pathways including those that regulate cytoskeleton, cellular motility, cytokinesis, proliferation, apoptosis, transcription and nuclear signaling. Similarly, the altered glycolytic pathway, the so-called 'Warburg effect', rewires tumor cell metabolism to support the biosynthetic requirements of uncontrolled proliferation. There exists strong evidence for the critical role of the glycolytic pathway's rate limiting enzymes in promoting immunosuppression. Areas covered: We review the emerging roles of GTPase effector proteins particularly the p21 activated kinase 4 (PAK4) and nicotinamide biosynthetic pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) as signaling molecules in immune surveillance and the immune response. Expert opinion: In this expert opinion article we highlight the recent information on the role of GTPases and the metabolic enzymes on the immune microenvironment and propose some unique immune therapeutic opportunities.

Keywords: GTPase; NAD; NAMPT; NAMPT inhibitor; NAPRT; P21 activated kinases; PAK4; PAK4 inhibitor; PD-1; PD-L1; Ras; immune checkpoint.

Figure 1. GTPase and NAD signaling mediated immune suppression mechanisms

Tumors thrive in a milieu of different types of cells including fibroblasts and collagen. Tumor stromal cells regulate the function of several types of immune cells such as Tregs, TH17, macrophages and MDSCs. Mutant ras promotes canonical RAF-MAPK-ERK-MEK pathway and also activates the Rho GTPase effector protein PAK4. RAF and PAK4 regulate the expression of pro-pro-survival signaling molecules that directly promote immune checkpoint protein PD-1 activation. PD-1 in turn block proper activation of immune surveillance molecules. NAMPT, a rate limiting enzyme in NADPH turnover, can directly activate PD-1 expression.

Figure 2. Dual inhibition of PAK4 and NAMPT as a feasible strategy to re-ignite a compromised tumor immune micro-environment

PAK4 signaling is active during cancer, in response to oncogenes such as Ras and mediated by Rho GTPases including Rac. Hypoxia/Warburg effect promotes the salvage biosynthesis pathway. This in turn activates immune surveillance molecules, thereby suppressing ICI activity