Abstract 61P
Background
Cancer-associated fibroblasts (CAFs) are the most prominent stromal cells in the tumor microenvironment, playing a significant role in tumor progress. However, the specific mechanisms underlying CAF formation and their role in remodeling the tumor microenvironment remain unclear. Previous studies have demonstrated that tumor cell-released autophagosomes (TRAPs) can arrival to lung tissue and regulate the function of lung fibroblasts to form premetastatic niche.
Methods
Primary breast adipose fibroblasts (NFs) were obtained from fourth mammary fat pads of mice, and co-cultured with TRAPs for 48 hours. The chemokines in collected supernatant were measured by ELISA. The expression of PD-L1 on the surface of fibroblasts and the ability to inhibit T cells were measured by flow cytometry (FCM). DAMPs on the TRAP surface blocked by antibodies, and fibroblasts pretreated with inhibitors were used to detect the ligand receptors between TRAP and NFs. Mouse experiments were performed as follows: 1)Tumor-bearing mice were constructed using TRAP low-expression cell lines (Beclin1KD/Raba8a KD); 2) NFs and 4T1 cells, with or without TRAP stimulation, were mixed and implanted in mice to detect the proportion and function of various cells in the tumor microenvironment by FCM.
Results
In vitro experiments revealed that the proteins (HSP27/70) on the surface of TRAP bind to TLR4 on NFs, exerting their functions via the HSP27/70-TLR4-MyD88- NF-κB signal cascade, ultimately expressing higher levels of PD-L1. Compared to the normal control (NC) group, the proportion of neutrophils and monocytes in the tumor microenvironment decreased, opposite T cells increased. Furthermore, the ability of T cells to secrete IFN-γ partially recovered. The level of PD-L1 on the surface of fibroblasts decreased, and their ability to inhibit T cells weakened.
Conclusions
TRAPs induce the formation of inflammatory and immune-suppressive fibroblasts by secreting CXCL1/2 and CCL5 to attract neutrophils and monocytes to the tumor microenvironment. Additionally, TRAPs directly inhibit T cells, ultimately contributing to the formation of the tumor microenvironment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
X. Zhou, X. Wang, F. Zhu.
Funding
National Natural Science Foundation, China.
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
602P - COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib (Enco) + binimetinib (Bini) vs vemurafenib (Vemu) or Enco in patients (Pts) with BRAF V600-mutant melanoma
Presenter: Andrew Haydon
Session: Poster Display
Resources:
Abstract
603P - An individualised postoperative radiological surveillance schedule for IDH-wildtype glioblastoma patients (HK-GBM Registry)
Presenter: Jason Chak Yan Li
Session: Poster Display
Resources:
Abstract
604P - Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who progressed after prior VEGFR-targeted therapy: Outcomes from COSMIC-311 by BRAF status
Presenter: Marcia Brose
Session: Poster Display
Resources:
Abstract
606P - BRAF and NRAS mutations are associated with poor prognosis in Asians with acral-lentiginous and nodular cutaneous melanoma
Presenter: Sumadi Lukman Anwar
Session: Poster Display
Resources:
Abstract
607P - Single institutional outcomes of radiotherapy and systemic therapy for melanoma brain metastases in Japan
Presenter: Naoya Yamazaki
Session: Poster Display
Resources:
Abstract
608P - The efficacy of immune checkpoint inhibitors and targeted therapy in mucosal melanomas: A systematic review and meta-analysis
Presenter: Andrea Teo
Session: Poster Display
Resources:
Abstract
609P - The association between thyroid function abnormalities and vitiligo induced by pembrolizumab regarding prognosis in patients with advanced melanoma
Presenter: Moez Mobarek
Session: Poster Display
Resources:
Abstract
610P - Analyzing the clinical benefit of the evidence presented at these congresses and utilizing a standardized scale to quantify it will significantly enhance our understanding of the studies showcased, allowing for more objective evaluation and interpretation
Presenter: Charles Jeffrey Tan
Session: Poster Display
Resources:
Abstract
611P - ESMO-magnitude of clinical benefit scale (MCBS) scores for phase III trials of adjuvant and curative therapies at the 2022 ASCO annual meeting (ASCO22)
Presenter: Thi Thao Vi Luong
Session: Poster Display
Resources:
Abstract
612P - Is the juice worth the squeeze? Overall survival gain per unit treatment time as a metric of clinical benefit of systemic treatment in incurable cancers
Presenter: Vodathi Bamunuarachchi
Session: Poster Display
Resources:
Abstract