Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling.

Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown. The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS. CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2-/-MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis. Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.

Zheng Y ，Wang N ，Wang S ，Zhang J ，Yang B ，Wang Z ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

XIAOPI formula inhibits the pre-metastatic niche formation in breast cancer via suppressing TAMs/CXCL1 signaling.

Zheng Y ，Wang N ，Wang S ，Yang B ，Situ H ，Zhong L ，Lin Y ，Wang Z ... -  《Cell Communication and Signaling》

PMN-MDSCs accumulation induced by CXCL1 promotes CD8(+) T cells exhaustion in gastric cancer.

Myeloid-derived suppressor cells (MDSCs) accumulation in multiple tumor is associated with immune checkpoint inhibitors (ICIs) resistance. However, mechanisms of MDSCs in ICIs resistance of gastric cancer (GC) have not been thoroughly explored. In this study, we found that the PMN-MDSCs frequency rather than the M-MDSCs frequency was correlated with the survival of GC patients and CXCL1 induced PMN-MDSCs accumulation in GC. S100A8/A9 heterodimer, a hallmark of MDSCs, upregulated the CXCL1 expression in GC cells through the TLR4/p38 MAPK/NF-κB pathway. Notably, PMN-MDSCs exerted immunosuppressive effect through S100A8/A9. Mechanically, S100A8/A9 led to CD8+ T cells exhaustion including inhibiting CD8+ T cells glycolysis, proliferation and TNF-α and IFN-γ production, which was dependent on TLR4/AKT/mTOR pathway. In tumor-bearing mice, the CXCR2 antagonist SB225002 decreased PMN-MDSCs accumulation, increased CD8+ T cells infiltration in GC and further enhanced anti-tumor efficacy of anti-PD-1. Taken together, our study identified that CXCL1 induced PMN-MDSCs accumulation in GC, and unveiled how PMN-MDSCs promoted CD8+ T cells exhaustion, which may provide a potential therapeutic strategy for GC.

Zhou X ，Fang D ，Liu H ，Ou X ，Zhang C ，Zhao Z ，Zhao S ，Peng J ，Cai S ，He Y ，Xu J ... -  《-》

PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling.

Sprouse ML ，Welte T ，Boral D ，Liu HN ，Yin W ，Vishnoi M ，Goswami-Sewell D ，Li L ，Pei G ，Jia P ，Glitza-Oliva IC ，Marchetti D ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Visualization and quantification of in vivo homing kinetics of myeloid-derived suppressor cells in primary and metastatic cancer.

Hoffmann SHL ，Reck DI ，Maurer A ，Fehrenbacher B ，Sceneay JE ，Poxleitner M ，Öz HH ，Ehrlichmann W ，Reischl G ，Fuchs K ，Schaller M ，Hartl D ，Kneilling M ，Möller A ，Pichler BJ ，Griessinger CM ... -  《Theranostics》