The J110monoclonal antibody reacts with human PD-1（programmed death-1）also known as CD279。PD-1is a50-55kDa cell surface receptor encoded by the Pdcdcd1gene that belongs to the CD28family of the Ig superfamily.PD-1is transiently expressed on CD4and CD8thymocytes as well as activated T and velymphocytes and myeloid cells.PD-1expression declines after successfuinal in in in in in in of Addigations cd1mRNA is expressed in developing B lymphocytes during the pro-B-cell stage.PD-1’s structure includes a ITIM（immunoreceptor tyrosine-based inhibitory motif）suggesting that PD-1negatively regulates TCR signals。PD-1signals via binding its two ligands，PD-L1and PD-L2both members of the B7family.Upon ligand binding，PD-1signaling inhibits T-cell activation，leading to reduced proliferation，cytokine production，and T cell death.Additionally mune disease in mice as PD-1knockout animals show dilated cardiomyopathy，splenomegaly，and loss of peripheral tolerance.Induced PD-L1expression is common in many tumors including squamous cell carcinoma，colon adenocarcinoma，and breast adenocarcinoma.PD-L1overexpression ression ression ress increased resstance of tumoted is.In mouse models of melanoma，tumor growth can be transiently arrested via treatment with antibodies which block the interaction between PD-L1and its receptor PD-1.For these reasons anti-PD-1mediated immunotherapies are currently being explored as cancer treatments。
Sanlorenzo，M.，et al.（2018）。“BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti-PD-1 Antibody”Clin Cancer Res24（14）：3377-3385。PubMed
Purpose:BRAF and MEK inhibitors（BRAF/MEKi）favor melanoma-infiltrating lymphocytes，providing the rationale for current combinatorial trials with anti-PD-1antibody.A portion of melanoma cells may express PD-1，and anti-PD-1antibody could have a direct antitumor effect.Here，we explore whether BRAF/MEKi modulates of PD-1（+）melanoma cells，supporting an additional-lymphocyte-independent-basis for their therapeutic combination with anti-PD-1antibody.Experimental Design：With data mining and flow cytometry，we assessed PD-1，PD-L1/2expression on on on on melanoma cell lines（CCLE，N=61；validation cell lines，N=7）and melanoma tumors（TCGA，N=214）.We exploredin vitrohow BRAF/MEKi affect rates of PD-1（+），PD-L1/2（+）melanoma cells，and characterized the proliferative and putative stemness features of PD-1（+）melanoma cells。We tested the functional lymphocyte-independent effect of anti-PD-1 antibody alone and in combination with BRAF/MEKiin vitro同时，同时in vivoimmunodeficient murine model.Results:PD-1is consistently expressed on asmall subset of melanoma cells，but PD-1（+）cells increase to relevant rates during BRAF/MEKi treatment[7.3%（5.6-14.2）vs.1.5%（0.7-3.2），P=0.0156；N=7]，together with PD-L2（+）melanoma cells[8.5%（0.0-63.0）vs.1.5%（0.2-43.3），P=0.0312；N=7].PD-1（+）cells proliferate less than PD-1（-）cells（avg.65%less；t=7days）and are preferentially endowed with stemness features.In vivo，the direct anti-melanoma activity of PD-1blockage as monotherapy was negligigible，but its association with BRaF/MEKi significantly delayed the development of drug resistance and tumorrelapse.Conclusions:BRaF/Kimerates of lanoma cells that may sustaintumor relapse，providing alymphocyte-independent rationale to explore combinatory strategies with anti-PD-1antibody.Clin Cancer Res；24（14）；3377-85。
流动周期，流动周期
Yamane，H.，et al.（2015）。“Programmed cell death protein1and programmed death-ligand1are expressed on the surface of some small-cell lung cancer lines”Am J Cancer Res5（4）：1553-1557。PubMed
INTRODUCTION:Programmed cell death protein1（PD-1）and programmed death-ligand1（PD-L1）play a major role in suppressing the immune system during the formation of the PD-1/PD-L1 pathway，which transmits an inhibitory signal to reduce T cell activity.PD-L1is often expressed in various malignant tumors.In contrast，PD-1is generally observed in activated lymphocytes and myeloid-derived dendritiic cells.Of the malignant cells，only Jurkat cells under special and diols and contic ymphoma tissue cells express PD-1on their surface。EthODS:To clarify whether the PD-1/PD-L1pathway participates in the immunotolerance of small-cell lung cancer（SCLC）cells，we examined the expressions of PD-1and PD-L1on the cell surface of SCLC cell lines using flow cytometry and reverse transcription polymerase chain reaction.RESULTS:Among the four SCLC cell lines examined，only SBC-3expressed both PD-1and PD-L1.CONCLUSIONS:We demonstrated-PD1 les were co-expressed on the surface of SCLC cells.Although the biological implications of this remain unclear，we speculate that PD-1and its ligand on the SCLC cells may participate in the growth inhibition of tumor cells as reported in cytotoxic T cells。
流动周期，流动周期
Bennett，F.，et al.（2003）。“Program death-1engagement upon TCR activation has distinct effect on costimulation and cytokine-driven proliferation:attenuation of ICOS，IL-4，and IL-21，but not CD28，IL-7，and IL-15responses“J Immunol170（2）：711-718。PubMed
The program death1（PD-1）receptor and its ligands，PD-1ligand（PD-L）1and PD-L2，define anovel regulatory pathway with potential inhibitory effects on T，B，and monocyte responses.In the present study，we show that human CD4（+）T cells express PD-1，PD-L1，and PD-L2upon activation，and Abs to the receptor can be agonists or antagonists of the pathway.Under optimal conditions of stimulation，ICOS but not CD28costimulation can be prevented by PD-1engagement.IL-2levels induced by costimulation are critical in determining the outcome of the PD-1，inargenot in in in in in in in in in in in in in the protes of the PD-1 IL-2levelsproduced upon ICOS costimulation account for the greater sensitivity of this pathway to PD-1-mediated inhibition.Interestingly，exogenous IL-2，IL-7，and IL-15but not IL-4and IL-21can rescue PD-1 inhibition，suggesting that among these cytokines only that ivates STAincion5 STAT5 has been implicated in the maintenance of IL-2Ralpha expression，these results suggest that IL-7and IL-15 restore proliferation under conditions of PD-1engagement by enhancing high-affinity IL-2R expression and hence，IL-2responsiveness。
