Gsα deficiency in macrophages promotes tumor progression via the MAPK signaling pathway.

Abstract

Under diverse stimuli in the tumor microenvironment, tumor-associated macrophages (TAMs) are susceptible to polarize toward an immunosuppressive phenotype. Reprogramming TAMs is a promising strategy for cancer immunotherapy. As a downstream molecule of G protein-coupled receptors, the alpha subunit of the stimulatory G protein (Gsα) plays an indispensable role in the transduction of extracellular signals to intracellular signals. However, whether Gsα is responsible for the reprogramming and polarization of TAMs is largely unknown. Here, we demonstrate that Gsα deficiency in TAMs accelerates tumor growth and metastasis in B16 and MC38 tumor cells. Further investigations revealed that Gsα upregulates the expression of CD86, CCR5, Il1b and Nos2 and inhibits CD206 and Il10 expression, which facilitates the recruitment and antitumoral activity of TAMs and contributes to the increased effector activity of CD8⁺ T cells. Mechanistically, Gsα promotes the proinflammatory M1-like polarization of TAMs by increasing the phosphorylation of ERK, p38 and JNK in the MAPK signaling pathway. In summary, our study indicates that Gsα-deficient TAMs exhibit protumoral activity via the MAPK pathway, suggesting a novel potential target for cancer immunotherapy based on TAMs reprogramming. KEY MESSAGES: Deficiency of Gsα in TAMs accelerates tumor growth and metastasis in B16 and MC38 tumor models in vivo and in vitro. Further investigations reveal that Gsα upregulates expression of CD86, CCR5, Il1b and Nos2, and inhibits CD206 and Il10 expression, which facilitates antitumoral activity of TAMs. Mechanistically, Gsα promotes M1 polarization of TAMs via upregulating phosphorylation of ERK, p38 and JNK in MAPK signaling pathway.