S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models.

BACKGROUND: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. METHODS: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. RESULTS: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. CONCLUSIONS: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

Breast cancer is a complex disease, and not all patients respond well to existing treatments. In this study, we sought to understand why some patients with a specific type of breast cancer called triple-negative breast cancer respond poorly to current therapies. We also aimed to identify new treatments for these patients. We analyzed genetic data from breast cancer patients and identified a factor called S100A8/A9, which is linked to poor outcomes in early-stage cancer. We tested drugs that can reduce the levels of this factor in tumors and found promising results, especially when combined with another treatment called immunotherapy. Our findings suggest that S100A8/A9 could help predict how patients will respond to treatments, potentially leading to better therapies in the future.

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition.

It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.

Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.

Rational design of bimetallic photocatalysts based on plasmonically-derived hot carriers.

Hot carriers generated by plasmonic excitations have recently opened up new avenues in photocatalysis. The transfer of these energetic carriers to adjacent molecules can promote chemical transformations that are important for hydrogen generation by water splitting, CO2 reduction and degradation of organic pollutants. Here, we have developed and optimised a plasmonic hot-carrier catalytic system based on silica nanoparticles decorated with plasmonic gold nanoparticles as a source of hot carriers, equipped with platinum nanoclusters as co-catalyst for the enhancement of hot-carrier extraction. The latter plays a triple role by providing: a surface favourable for molecular adsorption; hot-electron generation near the nanoclusters due to field enhancement effects and electron momentum relaxation facilitating the electron transfer across the metal surface, exactly where molecules are adsorbed. The combination of plasmonic and catalytic metals in nano-heterostructured devices provides a new platform for photocatalytic processes and is of significant interest for future solar-based clean technologies.

3D Full-Color Image Projection Based on Reflective Metasurfaces under Incoherent Illumination.

Metasurfaces provide an efficient approach to control light wavefronts and have emerged at the forefront of digital holography. Nevertheless, full-color image projection remains challenging. Using a combination of specular and diffuse reflections from a metasurface, in analogy to the normal mapping technique, we designed a reflective metasurface performing in the whole visible spectral range to demonstrate 2D images with shading effects of 3D objects. The noninterleaved metasurface is based on aluminum nanostructures with high and relatively uniform efficiency across the visible spectrum. It operates under incoherent illumination and does not require polarizing optics to observe images. The integration of the metasurface behind pre-existing transparent color images is also demonstrated for introduction of 3D effects. Emulating color 3D images with flat metasurfaces can be useful for security applications and decorative purposes. The design of broadband metasurface diffusers is also interesting for flat optical diffusing elements with engineered properties and display technology.

Optimizing hot carrier effects in Pt-decorated plasmonic heterostructures.

Hot carrier generation by light in various semiconductors and metallic nanostructures is important for many photocatalytic and photochemical processes, including water and hydrogen splitting. Here, we report on investigations of hot electron generation and extraction from Pt decorated SiO2-Au nanoparticles using the degradation of methylene blue dye as a test-bed. Enhanced catalytic activity was found with an increase of Pt loading on the surface of the heterostructures. The small size of the Au nanoparticles (∼12 nm) decorating the silica nanoparticles reduces hot electron collisions and related thermalization processes, since charge carriers have short paths to the surface where reactions take place and where Pt is situated. The heterostructures exhibit a broad plasmonic resonance in the visible wavelength range from 500 to 700 nm and hot carrier generation predominately takes place under resonant excitation. Electron-microscopy characterization and numerical modelling have allowed the optimization of Pt coverage for hot-electron transfer, consisting of a thin Pt shell covering the Au nanoparticle with Pt nanoparticles additionally placed on top. This geometry provides an increased number of active sites for methylene blue degradation and promotes separation of charge carriers generated by plasmonic excitations in Au. Such SiO2-Au-Pt nanoparticles are attractive for hot-electron production due to the tunability of their plasmonic resonance and enhanced catalytic activity.

DNA-Assembled Plasmonic Waveguides for Nanoscale Light Propagation to a Fluorescent Nanodiamond.

Plasmonic waveguides consisting of metal nanoparticle chains can localize and guide light well below the diffraction limit, but high propagation losses due to lithography-limited large interparticle spacing have impeded practical applications. Here, we demonstrate that DNA-origami-based self-assembly of monocrystalline gold nanoparticles allows the interparticle spacing to be decreased to ∼2 nm, thus reducing propagation losses to 0.8 dB per 50 nm at a deep subwavelength confinement of 62 nm (∼λ/10). We characterize the individual waveguides with nanometer-scale resolution by electron energy-loss spectroscopy. Light propagation toward a fluorescent nanodiamond is directly visualized by cathodoluminescence imaging spectroscopy on a single-device level, thereby realizing nanoscale light manipulation and energy conversion. Simulations suggest that longitudinal plasmon modes arising from the narrow gaps are responsible for the efficient waveguiding. With this scalable DNA origami approach, micrometer-long propagation lengths could be achieved, enabling applications in information technology, sensing, and quantum optics.

Spontaneous emission in non-local materials.

Light-matter interactions can be strongly modified by the surrounding environment. Here, we report on the first experimental observation of molecular spontaneous emission inside a highly non-local metamaterial based on a plasmonic nanorod assembly. We show that the emission process is dominated not only by the topology of its local effective medium dispersion, but also by the non-local response of the composite, so that metamaterials with different geometric parameters but the same local effective medium properties exhibit different Purcell factors. A record-high enhancement of a decay rate is observed, in agreement with the developed quantitative description of the Purcell effect in a non-local medium. An engineered material non-locality introduces an additional degree of freedom into quantum electrodynamics, enabling new applications in quantum information processing, photochemistry, imaging and sensing with macroscopic composites.