Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from a

When It Takes a Network: Creating Strategy and Agility through Wargaming

When the basis of competition shifts from product features to an experience delivered by a network of independently acting participants in a complex and fast-evolving world, it creates new and unexplored challenges for strategy development and execution across organizational boundaries. Approaches based on reason are ineffective in these situations as reason alone will not inspire others to participate or motivate voluntary actions in the interest of a common purpose when conditions change unexpectedly. This paper looks at what it takes to effectively make strategy at the network level in the face of ill-defined and time-pressured conditions

Organisational forms and knowledge management: one size fits all?

In the new economy, a firm's sustainable competitive advantage flows from its ability to create and exploit new knowledge. Consequently, the need for executives to manage this process effectively is greater than ever. The extant knowledge management literature contains an implicit assumption that a standard approach with universal applicability to this process exists. Yet many organisations adopting this approach fail to realise the anticipated benefits. In this paper, the underlying causes for these failures are discussed and the assumption of a standard knowledge management approach critically challenged. To this end, the organisational form framework by Miles and Snow is integrated, for the first time, with the knowledge management models by Nonaka. Through the integration of these two frameworks, it is shown that the choice of knowledge management approach cannot be unqualified but must be closely aligned with the organisation's strategic and operational form in order for the anticipated benefits to be reaped. Our analysis suggests three conclusions: One, Prospector- type organisations will tend to adopt Bottom-Up approaches for effective knowledge creation; two, Defender-type organisations will tend to adopt Top-Down approaches; and three, Analyser types will adopt Middle-Up-Down knowledge creation approaches. We provide directions for future research

Roads to Resilience: Building Dynamic Approaches to Risk

In complex and constantly changing business environments with ever more complex risk, one of the key questions that boards ask of themselves is: “What can we do to future-proof ourselves against the growing array of risks?” In a search to answer this question, case study based research, undertaken by Cranfield School of Management on behalf of Airmic, looked at eight leading companies that constantly have to deal with significant uncertainty and risk and yet have survived, maintaining both their reputation and balance sheet. The ways they approach risk management and have achieved resilience was investigated at: AIG, Drax Power, InterContinental Hotels Group, Jaguar Land Rover, Olympic Delivery Authority, The Technology Partnership, Virgin Atlantic and Zurich Insurance.Crawford, Lockton & Pw

Project portfolio management: balancing risk and performance in turbulent times

When economic conditions become more challenging, organisations have fewer resources to deploy on new business or change projects and programmes, reducing the number of such initiatives they can undertake. However, at such times, the projects and programmes they do invest in are often more critical, since they may be essential to deliver efficiency savings, sustain revenue or improve aspects of performance on which the survival of the organisation can depend. The current turbulent economic conditions appear to have caused increasing adoption of project portfolio management (PPM) by organisations. PPM can be defined as: managing a diverse range of projects and programmes to achieve the maximum organisational value within resource and funding constraints, where 'value' does not imply only financial value and includes delivering benefits which are relevant to the organisation's chosen strategy