Dataset Information

MFGE8 induces anti-PD-1-therapy resistance by promoting extracellular vesicle sorting of PD-L1

ABSTRACT: To elucidate which secreted factors in tumor tissues (TTs) are responsible for the upregulation of UBE4A as the tumor progresses, we inoculated tumors in mice and analyzed the 2- and 4-week TT fluid by mass spectrometry (MS). By combining molecular weight cut off(MWCO) and the identification of secreted proteins, we identified three candidate proteins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: peihan wu

LAB HEAD: Zhijian Cai

PROVIDER: PXD058079 | Pride | 2025-05-07

REPOSITORIES: Pride

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			Action	DRS
	21071902_ZQ_812.mzid.gz	Mzid
	21071902_ZQ_812.mzid.gz_21071902_ZQ_812.MGF	Mzid
	21071902_ZQ_812.raw	Raw
	21071902_ZQ_812.sf3	Other
	21071902_ZQ_813.mzid.gz	Mzid

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MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1.

Wang Wenhui W Chen Jiming J Wang Shibo S Sun Xinhai X Yang Jie J Yu Pengfei P Hu Guinv G Wang Jiang J Zhang Jing J Qiao Shuya S Wang Jianli J Zhang Gensheng G He Yuzhou Y Feng Huajun H Cai Zhijian Z

Cell reports. Medicine 20250121 2

Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by ...[more]

PMID: 39842432

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Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. Methods: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, ChIP-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells, and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression/or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. Results: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched and IL-6 expression was higher in patients with no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. Conclusions: The tumor-cell-intrinsic function of PD-L1 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.