The research team of Prof. Chuanhe Zhiji and Prof. Taniguchi, from the Institute of Industrial Science, Osaka University, Japan, successfully used an electrical test method to successfully identify a molecule of a nucleic acid base that constitutes DNA (deoxyribonucleic acid).
The results of this study show that scientists can identify the identity of a unit of nucleic acid base based on the current value between the nanoelectrodes, and also verify the basic principles of next-generation DNA sequencing. The next generation of DNA sequencing technology can be a leap forward.
Not long ago, New England Journal of Medicine published an article entitled "Unmasking PD-1 Resistance by Next-Generation Sequencing", which describes how to expose the resistance of PD-1 antibodies with next-generation antibody sequence technology.
In recent years, the FDA has approved PD-1 antibodies for the treatment of various types of cancer, including melanoma, lung cancer, kidney cancer, classic Hodgkin's lymphoma, and head and neck cancer. However, even the most sensitive tumors (such as melanoma) are naturally resistant.
In a new study published in NEJM, scientists describe how to use genome-wide sequencing to identify the mechanisms behind tumor-producing immune resistance in PD-1 antibody treatment. The melanoma patients who participated in the study responded to pembrolizumab treatment for more than 6 months after relapse.
Tumors can resolve after blocking the PD-1/PD-L1 pathway and may be involved in the activation of tumor-infiltrating T cells. This small trial population consisted of four patients. Their initial response to PD-1 antibodies was a significant increase in tumor-infiltrating CD8-T cells. However, CD8-T cells were usually confined to the tumor margin when the disease relapsed.
In this study, the results of whole-genome antibody protein sequencing of tumor cell DNA integrated in vitro functional studies, gene expression analysis, and immunophenotypic data. The genetic variation detected in the study is related to two signaling pathways.
Changes in the first pathway result in a lack of response to interferon-gamma in tumor cells, involving functional deletion mutations in the genes encoding Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). The study found that the tumor did not detect JAK mutations at baseline, but this mutation occurred during recurrence. In vitro studies have shown that JAK mutations cause tumor cells to completely lose sensitivity to interferon-gamma.
The change of the second pathway is related to the escape mechanism of cytotoxic T cells (missing of MHC class I expression on the surface of tumor cells), specifically related to the gene encoding β-2-microglobulin (B2M). Truncating mutation.
Although the number of patients in this study is small, the conclusion is compelling. This is the first study to reveal that the drug resistance of PD-1 antibody immunotherapy is related to tumor cell gene mutation. Previously, scientists have uncovered the non-genetic or immunological mechanisms behind resistance to PD-1 therapy. The genomic mechanism revealed by this study is also complementary to previous studies.
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