MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer.

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC.

Rheological Properties of Different Graphene Nanomaterials in Biological Media.

Carbon nanomaterials have received increased attention in the last few years due to their potential applications in several areas. In medicine, for example, these nanomaterials could be used as contrast agents, drug transporters, and tissue regenerators or in gene therapy. This makes it necessary to know the behavior of carbon nanomaterials in biological media to assure good fluidity and the absence of deleterious effects on human health. In this work, the rheological characterization of different graphene nanomaterials in fetal bovine serum and other fluids, such as bovine serum albumin and water, is studied using rotational and microfluidic chip rheometry. Graphene oxide, graphene nanoplatelets, and expanded graphene oxide at concentrations between 1 and 3 mg/mL and temperatures in the 25-40 °C range were used. The suspensions were also characterized by transmission and scanning electron microscopy and atomic force microscopy, and the results show a high tendency to aggregation and reveals that there is a protein-nanomaterial interaction. Although rotational rheometry is customarily used, it cannot provide reliable measurements in low viscosity samples, showing an apparent shear thickening, whereas capillary viscometers need transparent samples; therefore, microfluidic technology appears to be a suitable method to measure low viscosity, non-transparent Newtonian fluids, as it is able to determine small variations in viscosity. No significant changes in viscosity are found within the solid concentration range studied but it decreases between 1.1 and 0.6 mPa·s when the temperature raises from 25 to 40 °C.