Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters

Abstract With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments

SUCCESSFUL TREATMENT OF OBSTRUCTIVE JAUNDICE IN A CARCINOMA OF THE PAPILLA OF VATER BY ENDOSCOPIC ULTRASOUND-GUIDED CHOLEDOCHODUODENOSTOMY

A 78-year-old man who was admitted to Akita University Hospital complained of jaundice andabdominal discomfort. He was diagnosed with obstructive jaundice that was caused by the carcinomaof the papilla of Vater based on the esophagogastroduodenoscopy (EGD) with a biopsy andcomputed tomography (CT). His condition was inoperable due to hepatic and lung metastasis,and he rejected any chemotherapy. Therefore, a palliative therapy to decompress the biliaryobstruction for the improvement of jaundice and the prophylaxis of cholangitis wasrequired. Although endoscopic retrograde biliary drainage (ERBD) was first attempted todecompress the biliary obstruction, it failed because of the tumor invasion. Next, endoscopicultrasound-guided choledochoduodenostomy (EUS-CDS) was carried out successfully, and thejaundice improved with the decrease of the serum bilirubin values from 30.1 mg/dl to 6.1 mg/dl onthe day of his discharge. He left the hospital and maintained his quality of life

OBSERVATION OF A HIGH-ENERGY COSMIC-RAY FAMILY CAUSED BY A CENTAURO-TYPE NUCLEAR-INTERACTION IN THE JOINT EMULSION CHAMBER EXPERIMENT AT THE PAMIRS

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NUCLEAR-INTERACTIONS OF SUPER HIGH-ENERGY COSMIC-RAYS OBSERVED IN MOUNTAIN EMULSION CHAMBERS

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