PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondrial fragmentation following T-cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches

The role of private label in retail ecosystem

This conceptual study aims to understand the role of private label in the modern retail, using the theoretical framework of ecosystem in Service-Dominant Logic (S-D Logic) perspective. The hypothesis of the work is that the literature about service ecosystem could be useful to analyze the relationships and interactions between manufacturer companies, copackers, retail companies, logistics, and customers; in this sense, it is possible to explain how ‟relationships in the retail ecosystem are affected by specific institutions that define actor’s behaviourâ€. The aim is to understand if the private label in modern retail could be considered as institution of the retail ecosystem, or rather, a shared language and code that affects production, retailers, customers and other actors who should contribute to value co-creation. The main managerial implications of the paper concern the marketing and management competences and knowledge necessary for retailers to manage an institution of increasing importance for the entire retail ecosystem, which generates economic, social and environmental value

Dual quality and limits to international adaptation of product quality: development of a conceptual framework and research agenda

In recent years, consumers and public authorities in Europe have shown growing attention to dual quality, a term that refers to the sale across European countries of seemingly identical products that have different compositions and levels of quality. This phenomenon has raised consumer protection concerns and requires reflection on the ethical limits of local adaptation of firms' international marketing strategies. However, a lack of academic research on this topic remains. The present work addresses this gap and develops a conceptual framework that integrates prior research on consumer perceptions of and reactions to product quality and studies the standardisation - adaptation dilemma inherent in firms' international marketing strategies. The arguments presented here result in the development of a framework that comprises five stages: firms' real motivations for employing dual quality, dual-quality implementation, consumer awareness of dual quality, perceived acceptability of dual quality and consumer reactions to dual quality. Drawing on this framework, a rich research agenda is proposed to guide future studies and provide policymakers with new insights to help them evaluate whether or not to intervene to protect consumers