Regulation of PD-1 in T cells for cancer immunotherapy.

Study of the molecular mechanisms underlying cancer immune escape is one of the core issues in immuno-oncology research. Cancer cells can evade T cell cytotoxicity by exploiting the upregulation of T cell inhibitory receptors on T cells and their ligands on cancer cells. These upregulated proteins include the inhibitory receptor programmed cell-death protein 1 (PD-1) and its ligand programmed cell death 1 ligand 1 (PD-L1), which can induce T cell exhaustion and reduce T cell activation. Characterizing PD-1 regulation will help to elucidate the molecular mechanisms underlying T cell exhaustion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-1 during gene transcription, post-transcriptional regulation, and post-translational modification and influence the effects of the anticancer immune response by targeting PD-1. In this review,we summarize the mechanisms of PD-1 regulation in T cells.

Yu X ，Gao R ，Li Y ，Zeng C ... -  《-》

Inhibition of T-cell-mediated immune response via the PD-1/ PD-L1 axis in cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8+ T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-γ), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-γ increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-γ treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-γ-induced PD-L1 expression. After 48 h co-incubation, CD8+ T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-γ further increased CD8+ T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-L1/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients; however, further in vivo and clinical studies are required.

Suriyo T ，Fuangthong M ，Artpradit C ，Ungtrakul T ，Sricharunrat T ，Taha F ，Satayavivad J ... -  《-》

Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker.

Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD-1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD-L1 (programmed cell death-ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD-1/PD-L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti-PD-1 monoclonal antibody Nivolumab, Pembrolizumab, and anti-PD-L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long-term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD-1 or PD-L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti-PD-1/PD-L1 drug resistance in tumors, the potential biomarkers for predicting PD-1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long-term clinical efficacy.

Wang Z ，Wu X 《-》

Editorial: T Cell Exhaustion.

Bonorino C ，Mognol G 《Frontiers in Immunology》

Firing Up Cold Tumors.

Elucidating how tumor-intrinsic pathways regulate T cell infiltration in tumors is crucial for developing new therapeutic strategies for immune checkpoint blockade therapy. Here, we review recent progress on how these pathways orchestrate immune status in tumors and discuss the potential interventions for reprogramming the tumor microenvironment for cancer treatment.

Cheng WC ，Ho PC 《Trends in Cancer》