Natural killer cell mediated killing of patient-derived lung cancer models in co-culture: An approach to unravel killing mechanisms.

Lung cancer is the most common malignancy and the leading cause of cancer mortality worldwide and the limited understanding of the complex interplay between the immune system and tumor cells hampers the development of novel therapies (Sung, 2021). Natural killer (NK) cells are lymphocytes and are highly cytotoxic against transformed cells without prior sensitization and thus play an important role in the development of lung cancer and other tumor types. It was shown that a NK cell gene signature within the tumor leads to a better overall survival (Habif, Crinier, Andre, Vivier, & Narni-Mancinelli, 2019; Larsen, Gao, & Basse, 2014; Takanami, Takeuchi, & Giga, 2001). The importance of NK cells in anti-tumor immunity is indisputable, but during tumor progression cancer cells escape their cytolytic function with various mechanisms (Sordo-Bahamonde, Lorenzo-Herrero, Payer, Gonzalez, & Lopez-Soto, 2020). This work aims to unravel dynamics between NK cells and lung cancer cells, investigating the prospects of cancer cell vulnerability, mechanisms of cell death and dynamics within short- and long-term co-culture. In this work I established a co-culture system of the human NK cell line NK-92 and patient-derived lung cancer cell lines in 2D and 3D to measure and mechanistically dissect NK cell killing efficacy. NK-92 were able to induced cell death in the majority of cell lines with a heterogenous pattern of killing efficacy between the individual lung cancer cell lines. Key findings of this work were; firstly, the identification of an epithelial-to-mesenchymal phenotype (EMT) gene signature in NK resistant cancer cell lines also reflected in a reduced killing of TGF treated cell lines; secondly, increased IFN signaling for highly sensitive cell lines; and thirdly, elevated cell death levels and less effect of caspase inhibition in highly vulnerable cancer cells

A Guide to Ground in Kant's Lectures on Metaphysics

While scholars have extensively discussed Kant’s treatment of the Principle of Sufficient Ground in the Antinomies chapter of the Critique of Pure Reason, and, more recently, his relation to German rationalist debates about it, relatively little has been said about the exact notion of ground that figures in the PSG. My aim in this chapter is to explain Kant’s discussion of ground in the lectures and to relate it, where appropriate, to his published discussions of ground

Ontology as Transcendental Philosophy

How does the critical Kant view ontology? There is no shared scholarly answer to this question. Norbert Hinske sees in the Critique of Pure Reason a “farewell to ontology,” albeit one that took Kant long to bid (Hinske 2009). Karl Ameriks has found evidence in Kant’s metaphysics lectures from the critical period that he “was unwilling to break away fully from traditional ontology” (Ameriks 1992: 272). Gualtiero Lorini argues that a decisive break with the tradition of ontology is essential to Kant’s critical reform of metaphysics, as is reflected in his shift from “ontology” to “transcendental philosophy,” two notions that Lorini takes to be related by mere “analogy” (Lorini 2015). I agree with Lorini that a thorough reform of ontology is a pivotal part of Kant’s critical plan for metaphysics and that ontology somehow “survives within the critical philosophy” (Lorini 2015: 76). To make this case, however, I deem it important to identify “ontology” and “transcendental philosophy” in the sense of extensional equivalence. While we can detect this identification in Kant’s writings, only from his metaphysics lectures can we get a full sense of its historical and philosophical significance. In this chapter I focus on how it represents a definitive turn from as well as notable continuity with traditional treatments of ontology, particularly the Wolffian one

The European External Action Service’s influence in European security and defence policy: understanding the role of its relational capital

Ten years after its institutionalisation, there remains little understanding of the European External Action Service’s (EEAS) role, its impact and the extent of its influence in the European security and defence policy-making process. This thesis aims to address this gap by answering whether, to what extent and how the EEAS has the ability to purposefully steer and shape European security and defence policies so that policies’ development and/or outcome is affected. More specifically, what enables or constrains the EEAS’s ability to influence policies? In juxtaposition to the dominant discourse that highlights the EEAS’s scarce material capital, this thesis argues that in order to understand the EEAS’s influence in the policy-making process, it is necessary to analyse its relational capital, defined as the capabilities and resources the institution derives from its networks. The thesis explains how (1) the EEAS’s reach across the governance structure derived from its embeddedness in a policy’s network governance and (2) the use of its networks, may be as conducive for policy impact and/or influence as its formally derived material capital. While the first structural assessment delineates the extent of influence the EEAS may have, the second actor-centric assessment offers a more granular understanding of how and to what effect the EEAS uses its intra- and inter-institutional networks. It assesses how the EEAS mobilises intangible assets such as its human and social capital to wield trust and information. Drawing on 77 elite interviews, three case studies are studied, namely the drafting and implementation of the EU Global Strategy, the Permanent Structured Cooperation and the Civilian CSDP Compact - tackling the 'strategic’, civilian and military components of the Common Security and Defence Policy (CSDP). The findings of the thesis corroborate that capabilities derived from and resources mobilised through its relational capital enables or constrains the EEAS’s ability to shape and steer policies, and more significantly, explains the variation in the extent of influence observed. This research offers a two-fold contribution to the academic literature. Theoretically, by highlighting the relevance of relational over material capital for understanding an institution’s influence in European policy-making, it introduces an overlooked yet highly relevant approach to European Foreign Policy. Empirically, it offers an in-depth understanding of the role, impact and influence of the EEAS in an increasingly informal, transgovernmental European security and defence governance

Fichte and Hegel on recognition and slavery

In the first section of this essay I show how Hegel’s account of the struggle for recognition can be explained in terms of the role that Fichte accords to recognition in his deduction of the concept of right and, in particular, in terms of a problem to which this deduction gives rise. In the second section, I show how Hegel seeks to resolve this problem by means of his account of the struggle for recognition. Finally, in the third section, I show how Fichte’s and Hegel’s claims concerning the necessity of mutual recognition do not prevent them from regarding slavery as justified in certain circumstances, or at least as being as much the fault of the person enslaved as the person who has enslaved him or her, despite the fact that slavery represents one of the clearest possible examples of a situation in which mutual recognition is absent. One may therefore question the extent to which they regard mutual recognition as an absolutely fundamental norm of social relations. There is the difference, however, that Hegel’s position appears to be that mutual recognition becomes such a norm in the course of history, whereas Fichte implies that the absence of mutual recognition may be justified simply whenever an individual has failed to raise him-or herself to the level of a being whose attitude towards him-or herself as demonstrated through his or her actions is proof of a status that demands recognition from others

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8(+) T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients