The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC. The results show that the immune cell composition is fundamentally different in lung adenocarcinoma as compared with lung squamous cell carcinoma, and that neutrophils are the most prevalent immune cell type. Using T-cell receptor-β sequencing and tumour reactivity assays, we predict that tumour reactive T cells are frequently present in NSCLC. These results should help to guide the design of clinical trials and the direction of future research in this area.

SUMMARY Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. The DNA binding protein CTCF regulates a diverse array of epigenetic processes and is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation, and chemically induced cancer in a broad range of tissues. Ctcf+/− tumors are characterized by increased aggressiveness including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf+/− tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome-wide. These findings establish CTCF as a prominent tumor suppressor gene and point to CTCF mediated epigenetic stability as a major barrier to neoplastic progression.

In patients with COPD, Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with ICIs. This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.

Lung cancer – the leading cause of cancer-related deaths worldwide – is a heterogeneous disease comprised of multiple histologic subtypes that harbor disparate mutational profiles. Immune-based therapies have shown initial promise in the treatment of lung cancer patients but are currently limited by low overall response rates. We sought to determine whether the host immune response to lung cancer is predicated, at least in part, by histologic and genetic differences, as such correlations would have important clinical ramifications. Using mouse models of lung cancer, we show that small cell lung cancer (SCLC) and lung adenocarcinoma (ADCA) exhibit unique immune cell composition of the tumor microenvironment. The total amount of leukocyte content was markedly reduced in SCLC compared to lung ADCA, which was validated in human lung cancer specimens. We further identified key differences in immune cell content using three models of lung ADCA driven by mutations in Kras, Tp53, and Egfr. Although Egfr-mutant cancers displayed robust myeloid cell recruitment, they failed to mount a CD8+ immune response. In contrast, Kras-mutant tumors displayed significant expansion of multiple immune cell types, including CD8+ cells, regulatory T cells, IL17A-producing lymphocytes, and myeloid cells. A human tissue microarray annotated for KRAS and EGFR mutations validated the finding of reduced CD8+ content in human lung adenocarcinoma. Taken together, these findings establish a strong foundational knowledge of the immune cell contexture of lung ADCA and SCLC and suggest that molecular and histological traits shape the host immune response to cancer.

The comparison of coronary DSCT with QCA shows a very robust image quality and a high diagnostic accuracy in a patient-based as well as a per-segment analysis. Maximal sensitivity and NPV in the per-patient analysis show the strength of the technique in ruling out significant CAD.

The metameric organization of the insect body plan is initiated with the activation of gap genes, a set of transcription-factor-encoding genes that are zygotically expressed in broad and partially overlapping domains along the anteroposterior (AP) axis of the early embryo. The spatial pattern of gap gene expression domains along the AP axis is generally conserved, but the maternal genes that regulate their expression are not. Building on the comprehensive knowledge of maternal gap gene activation in Drosophila, we used loss- and gain-of-function experiments in the hover fly Episyrphus balteatus (Syrphidae) to address the question of how the maternal regulation of gap genes evolved. We find that, in Episyrphus, a highly diverged bicoid ortholog is solely responsible for the AP polarity of the embryo. Episyrphus bicoid represses anterior zygotic expression of caudal and activates the anterior and central gap genes orthodenticle, hunchback and Krüppel. In bicoid-deficient Episyrphus embryos, nanos is insufficient to generate morphological asymmetry along the AP axis. Furthermore, we find that torso transiently regulates anterior repression of caudal and is required for the activation of orthodenticle, whereas all posterior gap gene domains of knirps, giant, hunchback, tailless and huckebein depend on caudal. We conclude that all maternal coordinate genes have altered their specific functions during the radiation of higher flies (Cyclorrhapha).

Cardiac magnetic resonance imaging and echocardiography are currently regarded as standard modalities for the quantification of left ventricular volumes and ejection fraction. With the recent introduction of dual-source computedtomography (DSCT), the increased temporal resolution of 83 ms should also improve the assessment of cardiac function in CT. The aim of this study was to evaluate the accuracy of DSCT in the assessment of left ventricular functional parameters with cardiac magnetic resonance imaging (MRI) as standard of reference. Fifteen patients (two female, 13 male; mean age 50.8 +/- 19.2 years) underwent CT and MRI examinations on a DSCT (Somatom Definition; Siemens Medical Solutions, Forchheim, Germany) and a 3.0-Tesla MR scanner (Magnetom Trio; Siemens Medical Solutions), respectively. Multiphase axial CT images were analysed with a semiautomatic region growing algorithms (Syngo Circulation; Siemens Medical Solutions) by two independent blinded observers. In MRI, dynamic cine loops of short axis slices were evaluated with semiautomatic contour detection software (ARGUS; Siemens Medical Solutions) independently by two readers. End-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF) and stroke volume (SV) were determined for both modalities, and correlation coefficient, systematic error, limits of agreement and inter-observer variability were assessed. In DSCT, EDV and ESV were 135.8 +/- 41.9 ml and 54.9 +/- 29.6 ml, respectively, compared with 132.1 +/- 40.8 ml EDV and 57.6 +/- 27.3 ml ESV in MRI. Thus, EDV was overestimated by 3.7 ml (limits of agreement -46.1/+53.6), while ESV was underestimated by 2.6 ml (-36.6/+31.4). Mean EF was 61.6 +/- 12.4% in DSCT and 57.9 +/- 9.0% in MRI, resulting in an overestimation of EF by 3.8% with limits of agreement at -14.7 and +22.2%. Rank correlation rho values were 0.81 for EDV (P = 0.0024), 0.79 for ESV (P = 0.0031) and 0.64 for EF (P = 0.0168). The kappa value of inter-observer variability were amounted to 0.85 for EDV, ESV and EF. DSCT offers the possibility to quantify left ventricular function from coronary CT angiography datasets with sufficient diagnostic accuracy, adding to the value of the modality in a comprehensive cardiac assessment. The observed differences in the measured values may be due to different post-processing methods and physiological reactions to contrast material injection without beta-blocker medication.

The aim of this study was to assess the performance of a software tool for quantitative coronary artery analysis of computed tomography coronary angiography (CT-QCA) in comparison with invasive coronary angiography with quantitative analysis (CAG-QCA) as standard of reference. Two radiologists reviewed the CT angiography data sets (Siemens Sensation 64) of 25 patients, grading coronary artery stenoses visually and with a software tool (Circulation, Siemens). Twenty-three data sets with sufficient image quality were included in the final analysis. CAG revealed a total of 30 wall irregularities and 28 stenoses, of which 17 were graded as moderate and nine as hemodynamically significant. CT-QCA showed a better agreement to CAG-QCA, with a systematic overestimation of the degree of stenosis of 6.1% and limits of agreement of +36.1% and -23.9; the correlation coefficient was 0.82 (p < 0.0001). Using CT-QCA, sensitivity, specificity, and positive and negative predictive value were 89%, 100%, 89%, and 100%, respectively, for significant area stenoses greater than 75%. The positive predictive value for the visual assessment amounted to 53%. Interobserver variability between CT-QCA and visual assessment showed a kappa value of 0.72. In conclusion, software-supported CT-QCA makes it possible to quantify significant coronary artery stenoses automatically, with good agreement to CAG-QCA.