研究背景: 腫瘤相關巨噬細胞是腫瘤微環境中佔比最高的免疫細胞之一；大多數腫瘤相關巨噬細胞會極化成促腫瘤生長的M2型態，並透過下調第一型干擾素信號通路 (type I IFN pathway)，形成抗發炎及免疫抑制的微環境。我們先前的研究結果顯示，協助囊泡運輸的Rab37小GTP酶，會調節巨噬細胞中白介素-6的分泌來引發M2型極化。然而，Rab37在調節巨噬細胞M2型極化中的詳細機制仍未完全闡明。
研究目的: 本研究旨在探討Rab37在調節腫瘤相關巨噬細胞M2型極化中的潛在機制，並釐清Rab37在腫瘤相關巨噬細胞中的轉錄調控。
研究結果: 我們透過cDNA微陣列、基因富集分析 (gene set enrichment analysis) 和路徑分析 (pathway analysis) 發現，在Rab37缺失小鼠的骨髓源性巨噬細胞中，第一型干擾素信號路徑有上調的趨勢，並透過即時逆轉錄聚合酶連鎖反應分析也觀察到相同結果。反之，在小鼠巨噬細胞株中過表達Rab37則觀察到第一型干擾素信號路徑有下調的趨勢。值得注意的是，我們發現Rab37缺失的骨髓源性巨噬細胞的基因表達與M1型巨噬細胞呈現正相關，並與M2型呈負相關。接著，我們觀察到用肺癌細胞培養基以及兩種表觀遺傳藥物5-aza-dC和SAHA處理後，巨噬細胞中的Rab37表達有顯著增加，伴隨第一型干擾素信號路徑的下降，說明腫瘤微環境可能透過改變腫瘤相關巨噬細胞的表觀遺傳來刺激Rab37表達。為了研究Rab37如何調節第一型干擾素路徑，免疫螢光圖像及核質分離實驗表明在骨髓源性巨噬細胞中Rab37會在細胞質中結合信號轉導和轉錄激活因子1（Signal transducer and activator of transcription 1, STAT1），進而減弱STAT1入核，導致第一型干擾素信號通路的下調。機制上，免疫沉澱和結構域剔除實驗表明Rab37會與STAT1的核定位序列 (nuclear localization sequence) 相互作用，進而減弱STAT1入核以及第一型干擾素信號通路的下調。此外，免疫螢光圖像和免疫沉澱顯示，非活化態的Rab37主要與STAT1交互作用。臨床上，多重免疫螢光組織化學染色顯示，具有高Rab37+/CD163+/STAT1cytosol腫瘤相關巨噬細胞特徵的肺癌患者與癌症晚期和較差的存活率相關。
研究結論： 這些研究結果表明，Rab37透過在細胞質中與STAT1相互作用並減弱其入核的能力，導致第一型干擾素信號通路表達下降，進而促進M2型巨噬細胞的極化。此外，在腫瘤相關巨噬細胞中，Rab37+/CD163+/STAT1cytosol的表達特徵可以作為肺癌患者預後不良的生物指標。

Background: Tumor-associated macrophages (TAMs) are one of the most abundant populations of tumor-infiltrating immune cells in the tumor microenvironment (TME). Most TAMs are polarized into M2-type pro-tumoral macrophages, which can downregulate the type I interferon (IFN) signaling pathway, contributing to an anti-inflammatory and immunosuppressive TME. Our previous study revealed that Rab37, a small GTPase involving vesicle trafficking, regulates the secretion of interleukin-6 in macrophages to trigger M2 polarization. However, the detailed mechanism of Rab37 in regulating macrophage M2 polarization remains incompletely elucidated.
Purpose: This study aims to elucidate the potential mechanisms by which Rab37 regulates M2 polarization in TAMs and to clarify the transcriptional regulation of Rab37 expression within TAMs.
Results: Our cDNA microarray, gene set enrichment analysis (GSEA), and pathway analysis data revealed that the type I IFN signaling pathway was enriched in bone marrow-derived macrophages (BMDMs) from Rab37 knockout (KO) mice. In addition, the expression of type I IFN genes and IFN-stimulated genes (ISGs) were increased in BMDMs from Rab37 KO mice. In contrast, overexpression of Rab37 significantly downregulated the expression of type I IFN genes and ISGs in the RAW264.7 macrophage cell line. Notably, gene expression comparisons between Rab37 KO and M1/M2-type BMDMs showed that Rab37 KO BMDMs phenocopied M1 macrophages and negatively correlated with M2 macrophages. To further investigate the role of Rab37 in TAMs, we observed an increased expression of Rab37, followed by a decreased expression of type I IFN genes and ISGs in macrophage cells or BMDMs after treatment with lung cancer condition medium (CM) as well as two epigenetic drugs, 5-aza-dC and SAHA, indicating an epigenetic regulation of Rab37 in TAMs. To investigate how Rab37 regulates type I IFN pathway, immunofluorescence (IF) images and nuclear fractionation assays further demonstrated that signal transducer and activator of transcription 1 (STAT1) translocated into the nucleus more in Rab37 KO BMDMs, while co-localized with Rab37 in the cytosol of the WT BMDMs. Mechanistically, immunoprecipitation (IP)-Western blot, reverse-IP, and domain mapping assays demonstrated that Rab37 interacted with the nuclear localization sequence of STAT1, attenuating its transcription regulation at the type I IFN genes and ISGs in macrophages. Moreover, IF images and IP-WB demonstrated that GDP-bound Rab37 predominantly interacted with STAT1 in the cytosol of macrophages. Clinically, the multiplex IF-immunohistochemistry assay indicated that lung cancer patients with the high Rab37+/CD163+/STAT1cytosol TAM profile correlated with advanced tumor stages and poor overall survival.
Conclusion: These results suggested that Rab37 promotes M2 macrophage polarization by interacting and sequestering STAT1 in the cytosol to inactivate the type I IFN signaling pathway. The expression profile of Rab37+/CD163+/STAT1cytosol in TAMs serves as a biomarker for poor prognosis in lung cancer patients.

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