BackgroundAlpha-fetoprotein (AFP) is a tumor-associated glycoprotein that functions in regulation of both ontogenic and oncogenic growth. Recent study showed that AFP can induce apoptosis or impair monocyte-derived dendritic cell (MDDC) function. However, it is still unclear which AFP domain (D-AFP) plays major role in this function.ResultsAs expected monocytes cultured in the presence of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin-4 (IL-4) developed into MDDC. Up-regulation of HLA-DR and CD11c as well as loss of CD14 molecules could be observed. Full length AFP (FL-AFP), domain 2 AFP (D2-AFP) and D3-AFP, but not D1-AFP, significantly inhibited the expression of HLA-DRhigh/CD11chigh and CD80+/CD86high molecules. In contrast, CD83 expression was substantially down-regulated in all samples. Expression of CD40 was significantly suppressed by FL-AFP but not by any D-AFPs. Finally, both FL-AFP and D-AFP impaired the MDDC ability to secrete IL-12 (p70).ConclusionsD2- and D3- but not D1-AFP extensively suppresses the MDDC function. All the recombinant AFP proteins impaired the ability of MDDC to secrete IL-12.
Background: Tumor cells express programmed death ligand-1 (PD-L1) through several biological processes, thereby having different clinical significance depending on the underlying mechanism of expression. Currently, mechanisms leading to PDL1 gene expression in colorectal cancer (CRC) are not fully understood. Methods: We investigated 98 Indonesia CRC patients to determine PD-L1 protein expressions and their correlations with PD-L1 gene copy number status, tumor infiltrating lymphocytes (TILs), tumor mutational profile, as well as clinicopathologic features. Results: Our investigation demonstrated that 18% of patients positively expressed PD-L1. Further analysis on PD-L1 copy number revealed that all PD-L1 + tumors had normal copy number, indicating that the expression of PD-L1 was not a consequence of genetic amplification of PD-L1. From TILs analysis, there was a significant increase of CD8 in all tumor cells expressing PD-L1 (P=0.0051), indicating that the inducible PD-L1 expression was the prominent mechanism occurred in CRC. Furthermore, the expression of PD-L1 in this CRC population was significantly associated with high frequency of MSI compared to the remainder PD-L1tumors (P=0.0001), suggesting the natural immunogenicity of tumors via MSI status plays role in attracting immune response. On the other hand, p53 mutations which were frequently observed within Indonesian CRCs (76.5%), they were not associated with PD-L1 expression (p=0.1108), as well as KRAS gene (29.6%; p=0.5772) and BRAF gene mutations (5%; p=0.2171). Conclusion: Our study demonstrated that PD-L1 expressions in CRC were predominantly found as a consequence of infiltrating CD8 T lymphocytes that in part arise in the setting of microsatellite instability. Taken together, our findings further support the role of adaptive immune resistance to drive PD-L1 induction in tumor microenvironment and may provide important rationale for strategy implementation of immunotherapy for CRC cases.
Latar belakang: Alfa fetoprotein (AFP) merupakan antigen onkofetal yang berperan penting dalam perkembangan ontogenik dan onkogenik. Kadar AFP dalam darah pasien hepatocellular carcinoma (HCC) diketahui meningkat dibandingkan orang sehat. Publikasi terakhir menunjukkan bahwa AFP menyebabkan disfungsi sel dendritik derivat monosit sebagai antigen presenting cell (APC) yang dapat mengakibatkan respon antitumor menjadi tidak efisien. Penelitian pendahuluan ini bertujuan untuk mengetahui apakah efek AFP terhadap disfungsi sel dendritik derivat monosit sebagai APC adalah melalui jalur sinyal NF-κB dengan menggunakan lipopolisakarida (LPS) sebagai penginduksi aktifasi NF-κB. Metode: Sel monosit dikultur dalam medium yang mengandung GM-CSF (800 ng/mL) dan IL-4 (1000 ng/mL) dengan atau tanpa penambahan AFP dan diinkubasi selama enam hari agar berdiferensiasi menjadi sel dendritik imatur. Sel dendritik matur kemudian diperoleh dengan menambahkan LPS ke kultur dan diinkubasi selama 30 menit. Deteksi translokasi NF-κB dilakukan menggunakan uji imunofluoresens (IFA). Hasil: Pada kelompok kontrol, induksi LPS menyebabkan terjadinya translokasi NF-κB sedangkan kelompok AFP menunjukkan hasil yang berlawanan yaitu translokasi NF-κB tidak terjadi.
More studies to evaluate the correlation of these with response from immunotherapy agents are warranted. Immunotherapy specific response data, survival, and predictive biomarkers of response will be reported in a future analysis. This study highlighted the importance to test for both of these markers in order to identify a patient subset that may benefit from immunotherapy. Legal entity responsible for the study: Shayma M. Kazmi Funding: None Disclosure: S.M. Kazmi: Speaker for Merck and Eisai. 36P Expression pattern of immune checkpoints programmed death (PD-1) and programmed death-ligand (PD-L1) in retinoblastoma and its prognostic significance
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