“…We then analyzed the expression levels of M1 and M2 markers between normal and cancer tissues. Due to the increased scavenging capabilities of M2 macrophages, CD163, CD206, VCAM1, ARG1, IL-10, and CD204 have been proposed as markers of M2-type macrophages [ 36 ]. While M1 macrophages have been reported to have increased antigen processing, presentation, and killing properties.…”
Background
The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients.
Methods
We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para‐tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured.
Results
Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα+ or PD1+ TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non‐HBV‐infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis.
Conclusion
Hyperactivated CD47/SIRPα and PD1/PD‐L1 signals in CD68+ TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.
“…We then analyzed the expression levels of M1 and M2 markers between normal and cancer tissues. Due to the increased scavenging capabilities of M2 macrophages, CD163, CD206, VCAM1, ARG1, IL-10, and CD204 have been proposed as markers of M2-type macrophages [ 36 ]. While M1 macrophages have been reported to have increased antigen processing, presentation, and killing properties.…”
Background
The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients.
Methods
We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para‐tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured.
Results
Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα+ or PD1+ TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non‐HBV‐infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis.
Conclusion
Hyperactivated CD47/SIRPα and PD1/PD‐L1 signals in CD68+ TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.
“…Compared with our previous studies using exosome as a carrier (Li et al., 2022 ), the significance of using HSA as a carrier to encapsulate IL-10 pDNA and DSP is that HSA has the advantages of simple production and low cost, and it’s its favorable targeting property (Lin et al., 2011 ; Chen et al., 2017 ; Tian et al., 2017 ). Compared with albumin nanoparticles loaded with a single drug, our double-drug loaded nanoparticles had the advantage of high drug loading ( Figure 1(A) ).…”
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is characterized by synovial inflammation and autoimmunity. The main cause of the disease is the imbalance of the proportion of pro-inflammatory macrophages (M1-type) and anti-inflammatory macrophages (M2-type) in the synovial tissues of the joint. To restore this balance, in our study, the interleukin-10 encoding anti-inflammatory cytokines (IL-10 pDNA) and chemotherapeutic drug dexamethasone sodium phosphate (DSP) were co-loaded into human serum albumin (HSA) preparing pDNA/DSP-NPs to actively target macrophages in synovium tissue to promote M1-M2 polarization. Confocal laser scanning microscope and western blot were used to demonstrate the targeting ability of co-delivery nanoparticles.
In vivo
, the real-time fluorescence imaging system and HPLC were used to study the tissue distribution and pharmacokinetics of nanoparticles, and the results showed that the accumulation of nanoparticles in the inflammatory joint site was higher. Its pharmacodynamics were evaluated in collagen-induced arthritis (CIA) rat model, and it demonstrated that the pDNA/DSP-NPs significantly reduced the expression of serum inflammatory factors and alleviated joint swelling and bone erosion, suggesting the favorable therapeutic effect. The synergistic treatment effect of IL-10 pDNA and DSP in this system was achieved by reducing the secretion of pro-inflammatory factors (TNF-α, IL-1β) and increasing the expression of anti-inflammatory factors (IL-10) to promote the M1-M2 polarization of macrophages. Our strategy is promising for co-delivery of gene drugs and chemical drugs by biomimetic natural materials to promote macrophages polarization so that to achieve synergically treatment of inflammatory disease.
“…The samples were then fractionated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred electrophoretically to a polyvinylidene fluoride membrane. The membrane was treated with 5% non-fat dry milk for 2 h in washing medium to block non-specific binding sites, then incubated with primary antibodies against TSG101, CD81, or CD9 (1:1000; Abcam, UK) [ 38 ] at 4 °C overnight. After washing with TBST, the membrane was incubated with horseradish peroxidase-conjugated anti-rabbit secondary antibody (1:1000; Beyotime Biotechnology) at room temperature for 1 h. The membrane was finally soaked in chemiluminescent HRP substrate (Solarbio Biotechnology Company), and chemiluminescence was measured with a ChemiDoc instrument (Bio-Rad, Hercules, CA, USA).…”
Section: Methodsmentioning
confidence: 99%
“…The resulting drug delivery system (FPD/MV/MTX@ZIF-8) exhibited enhanced drug loading capacity, controlled drug release under acidic conditions, good biocompatibility, and prolonged time in circulation [ 36 ]. In our previous work, we achieved only 20% dexamethasone loading in exosomes [ 37 ], and the DLE was 3.49% for plasmid DNA encoding the anti-inflammatory cytokine interleukin-10 and 9.67% for betamethasone sodium phosphate into biomimetic vector M 2 exosomes [ 38 ], while we achieved much higher loading of 70% with FPD/MV/MTX@ZIF-8. Scheme 1 Schematic illustration of the procedure of preparing biomimetic FPD/MV/MTX@ZIF-8 nanoparticles for targeting and intracellular delivery of drugs …”
Background
Methotrexate (MTX) has been highlighted for Rheumatoid arthritis (RA) treatment, however, MTX does not accumulate well at inflamed sites, and long-term administration in high doses leads to severe side effects. In this study, a novel anti-RA nanoparticle complex was designed and constructed, which could improve the targeted accumulation in inflamed joints and reduce side effects.
Results
Here, we prepared a pH-sensitive biomimetic drug delivery system based on macrophage-derived microvesicle (MV)-coated zeolitic imidazolate framework-8 nanoparticles that encapsulated the drug methotrexate (hereafter MV/MTX@ZIF-8). The MV/MTX@ZIF-8 nanoparticles were further modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate (polyethylene glycol)-2000] (hereafter FPD/MV/MTX@ZIF-8) to exploit the high affinity of folate receptor β for folic acid on the surface of activated macrophages in RA. MTX@ZIF-8 nanoparticles showed high DLE (~ 70%) and EE (~ 82%). In vitro study showed that effective drug release in an acidic environment could be achieved. Further, we confirmed the activated macrophage could uptake much more FPD/MV/MTX@ZIF-8 than inactivated cells. In vivo biodistribution experiment displayed FPD/MV/MTX@ZIF-8 nanoparticles showed the longest circulation time and best joint targeting. Furthermore, pharmacodynamic experiments confirmed that FPD/MV/MTX@ZIF-8 showed sufficient therapeutic efficacy and safety to explore clinical applications.
Conclusions
This study provides a novel approach for the development of biocompatible drug-encapsulating nanomaterials based on MV-coated metal-organic frameworks for effective RA treatment.
Graphical Abstract
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