The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies.

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.

PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Comparison of respiratory system impedance in asthma and COPD: A prospective observational study.

BACKGROUND AND OBJECTIVE: A single assessment of within-breath variations of respiratory system reactance (Xrs) at 5 Hz (ΔX5) measured by the forced oscillation technique (FOT) has been reported to be useful for the detection of pathophysiological changes in chronic obstructive pulmonary disease (COPD) and asthma. We examined longitudinal changes in respiratory system resistance (Rrs) and Xrs during tidal breathing between stable asthma and COPD patients in order to clarify the features of changes of respiratory system impedance and airflow limitation for these conditions. METHODS: Between April 2013 and September 2013, outpatients with a COPD or asthma diagnosis were recruited. We examined forced expiratory volume in 1 s (FEV1 ) and FOT every 6 months until September 2015. Annual changes were estimated from the linear regression curve slope. RESULTS: We included 57 and 93 subjects with COPD and asthma, respectively. The median follow-up period was 26 months (range: 24-29 months). Within-breath analysis showed that the difference between mean Rrs at 5 Hz and 20 Hz was significantly lower, and ΔX5 more negative, in COPD than in asthma patients. With regard to annual changes, only ΔX5 was significantly different, more negative, in COPD than in asthma patients. Comparing between COPD subjects of Global Initiative Chronic Obstructive Lung Disease (GOLD) stage I/II and those with asthma, there were no significant differences in respiratory system impedance at enrolment, while annual change in ΔX5 was significantly more negative in mild COPD than in asthma patients. CONCLUSION: ΔX5 may be useful for long-term assessment of airflow limitation in COPD.

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens.

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

Simultaneous presence of lung adenocarcinoma and malignant pleural mesothelioma: A case report.

The co-presence of malignant pleural mesothelioma (MPM) and lung cancer is rare. We report a 70-year-old male with exposure to asbestos. Chest computed tomography revealed a right mediastinal mass combined with an enlarged ipsilateral lymph node and left pleural effusion. Transbronchial lung biopsy revealed lung adenocarcinoma. Thoracoscopic examination revealed multiple left pleural nodules, leading to the diagnosis of MPM. Despite aggressive anticancer drug therapy, he expired due to disease progression 2.5 years after diagnosis. Autopsy confirmed an epithelioid MPM in the left pleura. MPM comorbidity in patients diagnosed with lung cancer should be considered, especially in those exposed to asbestos.

Impact of exacerbations on respiratory system impedance measured by a forced oscillation technique in COPD: a prospective observational study.

BACKGROUND: Forced oscillation technique (FOT) has been reported to be useful in the evaluation and management of obstructive lung disease, including COPD. To date, no data are available concerning long-term changes in respiratory system impedance measured by FOT. Additionally, although exacerbations have been reported to be associated with excessive lung function decline in COPD, the impact of exacerbations on the results of FOT has not been demonstrated. The aim of this study was to investigate the longitudinal changes in respiratory system impedance and the influence of exacerbations thereon. METHODS: Between March 2011 and March 2012, outpatients who attended Kobe City Medical Center West Hospital with a diagnosis of COPD were assessed for eligibility. Baseline patient characteristics (age, sex, body mass index, smoking history, current smoking status, COPD stage), lung function (post-bronchodilator forced expiratory volume in 1 second [FEV1]), blood tests (neutrophils and eosinophils), FOT, and COPD assessment test results were collected at enrollment. Lung function and FOT were examined every 6 months until March 2016. Annual changes in FEV1 and FOT parameters were obtained from the slope of the linear regression curve. The patients were divided into 2 groups based on exacerbation history. RESULTS: Fifty-one of 58 patients with COPD were enrolled in this study. The median follow-up period was 57 (52-59) months. Twenty-five (49%) patients experienced exacerbations. A significant annual decline in FEV1 and respiratory system impedance were shown. Additionally, annual changes in FEV1, respiratory system resistance at 5 Hz, respiratory system reactance at 5 Hz, and resonant frequency were greater in patients with exacerbations than in those without exacerbations. CONCLUSION: Exacerbations of COPD lead not only to a decline in lung function but also to an increase in respiratory system impedance.

The relationship between respiratory system impedance and lung function in asthmatics: A prospective observational study.

INTRODUCTION: The aim was to elucidate the relationship between the annual changes in respiratory system impedance, measured by FOT, and lung function tests in patients with asthma. METHODS: Between March 2011 and March 2012, asthma outpatients who attended Kobe City Medical Center West Hospital were recruited. Lung function tests, FOT were conducted every 6 months until March 2016. The relationships between annual parameter changes were evaluated. RESULTS AND CONCLUSION: Sixty-four patients were completed this study. The median follow-up period was 55 months. At enrollment, although resistance showed no relationship with forced expiratory volume in one second (%FEV1), the reactance was moderately correlated with X5 (r=0.524, r2=0.275, <0.001), Fres (r=-0.498, r2=0.248, <0.001) and ALX (r=-0.416, r2=0.173, p=<0.001). By contrast, the annual resistance change at 5Hz (R5) was highly and significantly associated with%FEV1 change (r=-0.564, r2=0.318, p<0.001). Longitudinal changes in airway resistance and reactance measured by FOT might be useful for the assessment of lung function in patients with asthma.

Three-dimensional imaging forced oscillation technique to assess position-dependent airway obstruction in relapsing polychondritis: A case report.

Relapsing polychondritis (RP) is characterized by recurrent systemic inflammation of the cartilages and is accompanied by central airway collapse. We report a case wherein three-dimensional imaging of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) by using MostGraph (CHEST M.I., Tokyo, Japan), a forced oscillation system, revealed that Rrs and Xrs in the inspiratory and expiratory phases correlated with proximal airway collapse. The degree of difference in Rrs and Xrs between the supine and sitting positions reflected airway collapse more closely than did the pulmonary function test. MostGraph could be a useful tool for assessing airway collapse in RP.

Acute eosinophilic pneumonia following heat-not-burn cigarette smoking.

A 20-year-old man was admitted with acute respiratory failure. He had started smoking 20 heat-not-burn cigarettes (HC) per day 6 months previously, then purchased a second device for smoking HC to increase smoking to 40 cigarettes per day 2 weeks before hospitalization. Acute eosinophilic pneumonia (AEP) was diagnosed based on medical history, chest high-resolution computed tomographic findings, and bronchoalveolar lavage fluid eosinophilia. On starting treatment with prednisolone, the patient exhibited complete recovery. A relationship between cigarette smoking and AEP has been suggested. HC were released in September 2015 in Japan, Italy, and Switzerland. HC attract attention as a cigarette generating less harmful substances than a conventional cigarette. We herein report the first case of AEP caused by smoking HC. HC are expected to spread around the world. In the same way as a conventional cigarette, HC should be recognized as a potential cause of AEP.

Drug-induced lung injury associated with combination therapy of daclatasvir and asunaprevir: The first case report.

Combination therapy with direct acting antiviral agents (DAAs) without interferon (IFN) has emerged as a treatment for chronic hepatitis C because of its high overall sustained virologic response rates and favorable side effect profile as compared to that with interferon. We report the first case of drug-induced lung injury (DLI) associated with IFN-free therapy with the DAAs, daclatasvir (NS5A inhibitor) and asunaprevir (NS3/4A protease inhibitor). Although this combination therapy of DAAs has been considered to have fewer side effects than IFN, more attention should be paid to DLI as an important side effect.

Pneumocystis pneumonia associated with human immunodeficiency virus infection without elevated (1 → 3)-ß-D glucan: A case report.

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii is one of the most common opportunistic infections in immunosuppressed patients, particularly in patients with acquired immunodeficiency syndrome (AIDS). (1 â†’ 3)-ß-D-glucan is a component of the cell wall of P. jirovecii and other fungi such as Candida sp., Aspergillus sp. and Histoplasma sp. The measurement of serum (1 â†’ 3)-ß-D-glucan has been reported to be a highly sensitive test for PCP related to human immunodeficiency virus (HIV-PCP). We report a case of HIV-PCP not associated with elevated serum (1 â†’ 3)-ß-D glucan and highlight how HIV-PCP cannot be completely ruled out if (1 â†’ 3)-ß-D glucan is negative.

Dual Emission and Mechanofluorochromism of a V-Shaped π-System Composed of Disulfonyl-Substituted Dibenzocyclooctatetraenes.

A series of dibenzocyclooctatetraenes 6 bearing phenylethynyl and phenylsulfonyl groups were synthesized from bromo-substituted formylbenzyl sulfone 4 via cyclic dimerization of 4 and Sonogashira coupling of the resulting dibromocyclooctatetraene 3 with terminal acetylenes. The diamino derivative 6b exhibited dual emission with emission maxima at 436 and 547 nm. Furthermore, in the fluorescence of 6b, solvatofluorochromism was observed in response to solvent polarity, whereas in the solid states, mechanofluorochromism was observed.

Metabolism of selegiline hydrochloride, a selective monoamine b-type inhibitor, in human liver microsomes.

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (K(m)=21.4 microM) and N-demethylation (K(m)=25.2 microM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4'-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19. In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.