Tumor-associated macrophage-derived exosomes LINC01592 induce the immune escape of esophageal cancer by decreasing MHC-I surface expression

Abstract

Background TAMs (tumor-associated macrophages) infiltration promotes the progression of esophageal cancer (EC). However, the underlying mechanisms remain unclear. Methods Abnormal expression of LINC01592 from EC microarrays of the TCGA database was analyzed. LINC01592 expression level was validated in both EC cell lines and tissues. Stable LINC01592 knockdown and overexpression of EC cell lines were established. In vitro and in vivo trials were conducted to test the impact of LINC01592 knockdown and overexpression on EC cells. RNA binding protein immunoprecipitation (RIP), RNA pulldown assays, and Immunofluorescence (IF) were used to verify the combination of E2F6 and LINC01592. The combination of E2F6 and NBR1 was verified through the utilization of ChIP and dual luciferase reporter assays. Results LINC01592 is carried and transferred by exosomes secreted by M2-TAMs to tumor cells. The molecular mechanism underlying the promotion of NBR1 transcription involves the direct binding of LINC01592 to E2F6, which facilitates the nuclear entry of E2F6. The collaborative action of LINC01592 and E2F6 results in improved NBR1 transcription. The elevation of NBR1 binding to the ubiquitinated protein MHC-I via the ubiquitin domain caused a higher degradation of MHC-I in autophagolysosomes and a reduction in MHC-I expression on the exterior of cancerous cell. Consequently, this caused cancerous cells to escape from CD8+ CTL immune attack. The tumor-promoting impacts of LINC01592, as well as the growth of M2-type macrophage-driven tumors, were significantly suppressed by the interruption of E2F6/NBR1/MHC-I signaling through the effect of siRNA or the corresponding antibody blockade. Significantly, the suppression of LINC01592 resulted in an upregulation of MHC-I expression on the tumor cell membrane, thereby enhancing the efficacy of CD8+ T cell reinfusion therapy. Conclusions The investigation conducted has revealed a significant molecular interaction between TAMs and EC via the LINC01592/E2F6/NBR1/MHC-I axis, which facilitates the progression of malignant tumors. This suggests that a therapeutic intervention targeting this axis may hold promise for the treatment of the disease.

MRPS16 promotes lung adenocarcinoma growth via the PI3K/AKT/Frataxin signalling axis

“…Using CCK‐8 (Cell Counting Kit‐8, Dojindo, Tokyo, Japan), a cell proliferation assay took place following the protocols. After seeding the cells into a 96‐well plate (5 × 10 5 cells/well) using an appropriate fresh medium and treating them with CCK‐8 solution, cell proliferation was determined treatment, measuring the absorption by a microplate reader (Bio‐Rad Laboratories, Hercules, CA, USA), with more available details in the previous publication 16–18 …”

Extracellular vesicles in neuroblastoma: role in progression, resistance to therapy and diagnostics

“…Accordingly, TAMs-released EVs were shown to promote EMT and angiogenesis by regulating the tumor cells and endothelial cells, thereby promoting metastasis in hepatic cancer ( 70 ). Several other studies have reported EV-mediated transmittance of pro-tumor signals between TAMs and the recipient tumor cells in multiple cancer types ( 71 , 72 ). These findings thus demonstrate an orchestrated EV-mediated network in cancer, which is although initiated by tumor cells but is contributed by several other tumor-supportive cells in the TME.…”

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

“…Moreover, M2 macrophages may transmit the long noncoding RNA (lncRNA) AFAP1-AS1 to ESCC cells via secreted exosomes, downregulating miR-26a expression and upregulating ATF2 expression, thereby promoting tumor cell invasion and metastasis in EC[ 95 ]. Furthermore, a recent study showed that exosomes secreted by M2 macrophages carrying LINC01592 could be transferred to EC cells, resulting in a decrease in MHC-I expression, thereby allowing tumor cells to escape from attacks by CD8 + CTLs[ 96 ]. When the E2F6/NBR1/MHC-I signaling pathway was disrupted by small interfering RNAs or corresponding blocking antibodies, the tumor-promoting effects induced by LINC01592, as well as M2-driven tumor growth, were significantly inhibited[ 96 ].…”

“…Furthermore, a recent study showed that exosomes secreted by M2 macrophages carrying LINC01592 could be transferred to EC cells, resulting in a decrease in MHC-I expression, thereby allowing tumor cells to escape from attacks by CD8 + CTLs[ 96 ]. When the E2F6/NBR1/MHC-I signaling pathway was disrupted by small interfering RNAs or corresponding blocking antibodies, the tumor-promoting effects induced by LINC01592, as well as M2-driven tumor growth, were significantly inhibited[ 96 ]. In summary, M2 macrophages play an inhibitory role in the TIME of EC and can be recognized as key regulators of cancer occurrence, progression and metastasis.…”

“…Moreover, allelic loss in the 6p21.3 region, observed in approximately 46.9% of ESCC patients in a Chinese study, has been shown to be associated with the downregulation of HLA class I antigens[ 108 , 109 ], and DNA hypermethylation may result in deficient expression of HLA class I genes in ESCC[ 110 ]. Numerous ncRNAs, such as miR-125a-5p and miR-148a-3p, may downregulate the expression of TAP2 and HLA-I to affect the antigen presentation process[ 111 ], and exosomal LINC01592 released from TAMs may also downregulate the expression of MHC-I in EC cells and promote malignant EC progression[ 96 ]. Downregulation of the expression of MHC molecules in the TME hampers antigen processing and presentation processes, thereby enabling tumor immune evasion in patients with EC.…”