8/6/2023 0 Comments Snapgene viewer citationHowever, the fundamental basis of our observation is not yet clear and needs further investigation by, e.g., cell experiments. Of note, we just recently revealed that expression of XP genes was predictive of response in two cohorts of anti-PD-1 treated melanoma patients. Remarkably, the immunological consequences of NER defects are far less explored than those of MMR and BER, although people suffering from the NER defect disease, xeroderma pigmentosum (XP), had an impressive response of their skin tumors to anti-programmed cell death-1 (PD-1) ICI in case reports. Besides MMR, there are two other pathways that repair DNA single-strand breaks (SSB): base excision repair (BER) and nucleotide excision repair (NER). food and drug administration for mismatch repair (MMR) deficient (or microsatellite instability-high) cancer. Certainly, the most prominent clinical example is the first site/tissue agnostic approval of pembrolizumab by the U.S. In the last years, the defects of different DNA repair pathways have been associated with an increased response to immune checkpoint inhibition (ICI) in cancer patients. The results of our study serve as the fundamental basis for the investigation of the immunological consequences of XPA disruption in melanoma. The better performance of the homozygous than the heterozygous mutated exon 1 cells in DNA damage repair (HCR) and post-UV-C cell survival (MTT), was associated with the expression of a novel XPA protein variant. In XPA exon 2, we generated a compound heterozygous mutated cell line ( c.206_208delTTG/c.208_209delGA p.I69_D70delinsN/p.D70Hfs*31). In XPA exon 1, we established a homozygous ( c.19delG p.A7Lfs*8) and a compound heterozygous ( c.19delG/c.19_20insG p.A7Lfs*8/p.A7Gfs*55) cell line. Based on their genetic sequence, candidates from XPA exon 1 and 2 were selected and further analyzed by immunoblotting, immunofluorescence, HCR and MTT assays. The resulting subclonal cell lines were investigated by Sanger sequencing. Therefore, we used CRISPR/Cas9 to disrupt XPA in A375 melanoma cells. The underlying mechanisms of this finding are still to be revealed. Recently, in melanoma patients, pretherapeutic XP gene expression was predictive for anti-programmed cell death-1 (PD-1) ICI response. In particular, patients with the nucleotide excision repair (NER) defect disease Xeroderma pigmentosum (XP) responded impressively well to ICI treatment. Defects in DNA repair pathways have been associated with an improved response to immune checkpoint inhibition (ICI).
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