Abstract
BACKGROUND: Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) primarily polarize into the M2-phenotype. Our previous study showed that the small GTPase Rab37 mediates IL-6 trafficking in macrophages for M2 polarization. Here, we uncover an unconventional role of Rab37, independent of vesicle trafficking, in promoting M2 polarization of TAMs. METHODS: The gene profiles in wild-type and Rab37 knockout (KO) bone marrow-derived macrophages (BMDMs) were analyzed using cDNA microarray. The mechanism of Rab37 in regulating the interferon (IFN) pathway was confirmed through in vitro/vivo assays and clinical studies. RESULTS: Type I IFN signaling was highly enriched in BMDMs from Rab37 KO mice. Moreover, Rab37 induction and decreased type I IFN genes were observed in macrophages treated with lung cancer-conditioned medium and epigenetic drugs, indicating an epigenetic regulation of Rab37 in TAMs. Mechanistically, GDP-bound Rab37 interacted with the nuclear localization sequence of STAT1 to sequest it in the cytosol from its transcription activities, thus leading to the downregulation of IFN genes. Clinically, CD163(+)/Rab37(+)/STAT1(cytosol) in TAMs expression signature correlated with advanced tumor stages and poor survival of lung cancer patients. CONCLUSIONS: Our findings highlight the cytosolic interaction of Rab37-STAT1 in M2 TAM polarization, with CD163(+)/Rab37(+)/STAT1(cytosol) TAMs as a lung cancer prognosis biomarker.