Abstract 6P
Background
Development of an immunosuppressive pre-metastatic microenvironment is a prerequisite for lung metastasis of breast cancer. However, previous mechanisms have focused on immune cells rather than vascular endothelial cells. Our previous research has shown that tumor cell-released autophagosomes (TRAPs) preferentially reaches the lung rather than breast cancer cells in the mouse model. Could the pre-arrival of TRAPs promote the immunosuppressive pre-metastatic microenvironment by acting on endothelial cells?.
Methods
TRAPs-treated ECs were subjected to transcriptome analysis. T cell function was detected by flow cytometry after co-culture of TRAP-treated ECs with T cells in vitro. We injected TRAPs into mice via the tail vein or established endogenous Becn1 knockdown 4T1 tumor cells model which reduced TRAPs release. Flow cytometry will be used to analyze Immunosuppressive function of PVECs and the late lung metastases was monitored. Antibody blocking assay and HMGB1 knockdown cell lines were used to detect key DAMP on the surface of TRAPs. Inhibitor-treated ECs and TLR4 knockout mice were used to detect corresponding functional receptors on the surface of ECs. CD/FillpinⅢ/CPZ -treated ECs to detect the movement of the cytoskeleton. Activation of signal pathways was detected by Western blot.
Results
TRAPs from breast tumor cell lines stimulated the upregulation of PD-L1 in PVECs via a HMGB1-TLR4–MyD88–p38/STAT3 signal cascade and depended on the movement of the cytoskeleton of ECs. TRAPs-treated ECs suppressed IFN-γ secretion and proliferation of CD4+ and CD8+ T cells in vitro and in vivo. Anti-PD-L1 treatment upregulated pulmonary T-cell function and reduced lung metastasis in tumor-bearing mice.
Conclusions
These findings elucidate a novel role and mechanism of TRAPs-induced immunosuppression of vascular endothelial cells in the pre-metastatic microenvironment. TRAPs or their surface HMGB1 represent important therapeutic targets to reverse immunosuppressive formation, while also providing a new theoretical basis for the treatment of early breast cancer with PD-L1 antibodies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Y. Wu, X. Zhou, C. Wu.
Funding
National Natural Science Foundation, China.
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
251P - LDH isozyme as a prognostic factor for patients with metastatic clear cell renal cell carcinoma (mCRCC)
Presenter: Hayato Takeda
Session: Poster Display
Resources:
Abstract
252P - Risk factors for recurrence after curative nephrectomy in non-metastatic renal cell carcinoma: A retrospective cohort study
Presenter: Kristine Tejada
Session: Poster Display
Resources:
Abstract
253TiP - WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma: A phase II multi-center study
Presenter: Yige Bao
Session: Poster Display
Resources:
Abstract
254TiP - Prospective observational trial of cabozantinib plus nivolumab in Japanese patients with advanced or metastatic renal cell carcinoma: JACUMET trial
Presenter: Yuji Miura
Session: Poster Display
Resources:
Abstract
264P - Interim results from a phase I study of AMG 509 (xaluritamig), a STEAP1 x CD3 XmAb 2+1 immune therapy in patients with metastatic castration-resistant prostate cancer (mCRPC)
Presenter: Chia-Chi Lin
Session: Poster Display
Resources:
Abstract
266P - Clinical application and potential impact of liquid biopsy on the management of Chinese patients with metastatic castration-resistant prostate cancer (mCRPC): A territory-wide prospective analysis
Presenter: Wai Kay Philip Kwong
Session: Poster Display
Resources:
Abstract
267P - Exploring homologous recombination deficiency threshold for predicting response to PARP inhibitor in prostate cancer
Presenter: Diwei Zhao
Session: Poster Display
Resources:
Abstract
268P - Comparisons of on new-onset prostate cancer in type 2 diabetes mellitus exposed to the SGLT2I and DPP4I: A population-based cohort study
Presenter: Hou In Chou
Session: Poster Display
Resources:
Abstract
269P - Prostate cancer harboring low COMT expression correlates with a poor prognosis and response to enzalutamide
Presenter: Shigekatsu Maekawa
Session: Poster Display
Resources:
Abstract
270P - Germline BRCA1/2 pathogenic variants in Japanese patients with prostate cancer are predictive factors for androgen receptor-axis-targeted therapy or chemotherapy for castration-resistant prostate cancer
Presenter: Shigekatsu Maekawa
Session: Poster Display
Resources:
Abstract