No abstract

Lung cancer is the second most common and the most lethal malignancy worldwide. It is estimated that lung cancer in never smokers (LCINS) accounts for 10-25% of cases, and its incidence is increasing according to recent data, although the reasons remain unclear. If considered alone, LCINS is the 7th most common cause of cancer death. These tumors occur more commonly in younger patients and females. LCINS tend to have a better prognosis, possibly due to a higher chance of bearing an actionable driver mutation, making them amenable to targeted therapy. Notwithstanding, these tumors respond poorly to immune checkpoint inhibitors (ICI). There are several putative explanations for the poor response to immunotherapy: low immunogenicity due to low tumor mutation burden and hence low MANA (mutation-associated neo-antigen) load, constitutive PD-L1 expression in response to driver mutated protein signaling, high expression of immunosuppressive factors by tumors cells (like CD39 and TGF-beta), non-permissive immune TME (tumor microenvironment), abnormal metabolism of amino acids and glucose, and impaired TLS (Tertiary Lymphoid Structures) organization. Finally, there is an increasing concern of offering ICI as first line therapy to these patients owing to several reports of severe toxicity when TKIs (tyrosine kinase inhibitors) are administered sequentially after ICI. Understanding the biology behind the immune response against these tumors is crucial to the development of better therapeutic strategies.

Prion protein (PrP) was initially described due to its involvement in transmissible spongiform encephalopathies. It was subsequently demonstrated to be a cell surface molecule involved in many physiological processes, such as vesicle trafficking. Here, we investigated the roles of PrP in the response to insulin and obesity development. Two independent PrP knockout (KO) and one PrP overexpressing (TG20) mouse models were fed high-fat diets, and the development of insulin resistance and obesity was monitored. PrP KO mice fed high-fat diets presented all of the symptoms associated with the development of insulin resistance: hyperglycemia, hyperinsulinemia, and obesity. Conversely, TG20 animals fed high-fat diets showed reduced weight and insulin resistance. Accordingly, the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was reduced in PrP KO mice and increased in TG20 animals. PrP KO cells also presented reduced glucose uptake upon insulin stimulation, due to reduced translocation of the glucose transporter Glut4. Thus, our results suggest that PrP reflects susceptibility to the development of insulin resistance and metabolic syndrome.

Diffuse large B-cell lymphoma can be classified into two prognostically distinct subgroups with germinal center B-cell-like (CG) and activated B-cell-like (post-CG) characteristics, based on CD10, BCL-6, and MUM1 expression. We performed a retrospective analysis of the clinical variables of 37 patients with primary mediastinal large B-cell lymphoma and the expression of BCL-6 and MUM1 in 22 patients with available tissue. The median age was 30 years, and 70% of the patients were female. BCL-6 and MUM1 were expressed in 64% and 45% of cases, respectively. Five-year overall survival (OS) and disease-free survival (DFS) were 47% and 81%, respectively. In univariate analysis, complete response (p = 0.0001), radiation therapy (p = 0.01), International Prognostic Index (p = 0.001), and MUM1 expression (p = 0.002) correlated with OS. For this group of patients with homogeneous clinical characteristics, response to initial chemotherapy and MUM1 expression were associated with prognosis.

Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic.