Taxanes remain one of the most effective medical treatments for breast cancer. Clinical trials have coupled taxanes with immune checkpoint inhibitors in patients with triple-negative breast cancer (TNBC) with promising results. However, the mechanism linking taxanes to immune activation is unclear. To determine if paclitaxel could elicit an antitumoral immune response, we sampled tumor tissues from patients with TNBC receiving weekly paclitaxel (80 mg/m2) and found increased stromal tumor-infiltrating lymphocytes and micronucleation over baseline in three of six samples. At clinically relevant concentrations, paclitaxel can induce chromosome missegregation on multipolar spindles during mitosis. Consequently, post-mitotic cells are multinucleated and contain micronuclei, which often activate cyclic GMP-AMP synthase (cGAS) and may induce a type I IFN response reliant on the stimulator of IFN genes (STING) pathway. Other microtubule-targeting agents, eribulin and vinorelbine, recapitulate this cGAS/STING response and increased the expression of immune checkpoint molecule, PD-L1, in TNBC cell lines. To test the possibility that microtubule-targeting agents sensitize tumors that express cGAS to immune checkpoint inhibitors, we identified 10 patients with TNBC treated with PD-L1 or PD-1, seven of whom also received microtubule-targeting agents. Elevated baseline cGAS expression significantly correlated with treatment response in patients receiving microtubule-targeting agents in combination with immune checkpoint inhibitors. Our study identifies a mechanism by which microtubule-targeting agents can potentiate an immune response in TNBC. Further, baseline cGAS expression may predict patient treatment response to therapies combining microtubule-targeting agents and immune checkpoint inhibitors.

CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

With advances in next generation sequencing (NGS) technologies, efforts have been made to develop personalized medicine, targeting the specific genetic makeup of an individual. Somatic or germline DNA Polymerase epsilon (PolE) mutations cause ultramutated (>100 mutations/Mb) cancer. In contrast to mismatch repair-deficient hypermutated (>10 mutations/Mb) cancer, PolE-associated cancer is primarily microsatellite stable (MSS) In this article, we provide a comprehensive review of this PolE-associated ultramutated tumor. We describe its molecular characteristics, including the mutation sites and mutation signature of this type of tumor and the mechanism of its ultramutagenesis. We discuss its good clinical prognosis and elucidate the mechanism for enhanced immunogenicity with a high tumor mutation burden, increased neoantigen load, and enriched tumor-infiltrating lymphocytes. We also provide the rationale for immune checkpoint inhibitors in PolE-mutated tumors.

This research examines how curriculum delivery predicts entrepreneurial skills, with knowledge of information and communication technology (ICT) as a mediator. Curriculum delivery with the multiple dimensions of objectives, contents, teaching strategies, and feedback and assessment was used in this study, and a quantitative research design was adopted. A questionnaire survey was used to collect data from 482 students at six universities in Lahore, Pakistan, and the partial-least-squares structural equation model in SmartPLS 3.2 was used for data analysis. The results show that all dimensions of curriculum delivery (i) do not influence entrepreneurial skills and (ii) positively influence the knowledge of ICT. Also, in the indirect relationships, all dimensions of curriculum delivery (i.e., objectives, contents, teaching strategies, and feedback and assessment) are associated positively with ICT knowledge. Therefore, ICT knowledge plays a mediating role between curriculum delivery and entrepreneurial skills. The results also show that curriculum delivery for educational entrepreneurs is not working effectively and efficiently in Pakistani universities, and it is concluded that curriculum delivery and ICT knowledge boost entrepreneurial skills. Finally, the conclusions, limitations, and practical implications of this study are presented in detail.