TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer.

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.

Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes.

Cellular deconvolution algorithms virtually reconstruct tissue composition by analyzing the gene expression of complex tissues. We present the decision tree machine learning algorithm, Kassandra, trained on a broad collection of >9,400 tissue and blood sorted cell RNA profiles incorporated into millions of artificial transcriptomes to accurately reconstruct the tumor microenvironment (TME). Bioinformatics correction for technical and biological variability, aberrant cancer cell expression inclusion, and accurate quantification and normalization of transcript expression increased Kassandra stability and robustness. Performance was validated on 4,000 H&E slides and 1,000 tissues by comparison with cytometric, immunohistochemical, or single-cell RNA-seq measurements. Kassandra accurately deconvolved TME elements, showing the role of these populations in tumor pathogenesis and other biological processes. Digital TME reconstruction revealed that the presence of PD-1-positive CD8+ T cells strongly correlated with immunotherapy response and increased the predictive potential of established biomarkers, indicating that Kassandra could potentially be utilized in future clinical applications.

In Vitro and In Vivo Evaluation of Infestation Deterrents Against Lice.

The human head louse is a cosmopolitan ectoparasite and frequently infests many people, particularly school-age children. Due to widespread pyrethroid resistance and the lack of efficient resistance management, there has been a considerable interest in the protection of uninfested people and prevention of reinfestation by disrupting lice transfer. In this study, two nonclinical model systems (in vitro and in vivo) were used to determine the efficacy of the infestation deterrents, Elimax lotion and Elimax shampoo, against human head lice or poultry chewing lice, respectively. With in vitro assessments, female head lice exhibited significantly higher avoidance responses to hair tufts treated with either of the test formulations, which led to significantly higher ovipositional avoidance when compared with female lice on control hair tufts. Additionally, both formulations were determined to be competent infestation deterrents in a competitive avoidance test in the presence of a known attractant (head louse feces extract). In in vivo assessments using a previously validated poultry model, Elimax shampoo was determined to be an efficacious deterrent against poultry chewing lice within Menopon spp. and Menacanthus spp.