Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Tackling Complex Social Challenges within Neoliberal Constraints : The Context Shaping ‘Intellectual Quality of Life’ (iQoL) in a Canadian University Context

The contemporary academic environment in Canada has undergone reorganization based on neoliberal principles, and has increased attention focused on the importance of supporting interdisciplinary initiatives to address complex problems affecting global society. The purpose of our study was to examine the experience of people participating in a specific university-funded interdisciplinary research initiative. As there is a strong emphasis within this program on reporting on the outcomes of the funding that supports interdisciplinary collaboration, our aim was to explore how participation may shape one’s intellectual quality of life (iQoL) and how one’s iQoL could be conceptualized and understood. Using a pragmatic constructivist case study, focus group and individual interviews were undertaken with 30 participants involved with university-funded interdisciplinary research teams. Findings illustrate that their iQoL was shaped by their capacity to engage in and achieve what they viewed as their core work and its outcomes. Related sub-themes addressed the social and relational climate, institutional environment and structure, and expectations and resources. We argue that further development of iQoL as a unique construct is required to adequately measure the full range of people’s experiences in academia, particularly when aiming to address ‘wicked’ social and global problems within a predominantly neoliberal context.Science, Faculty ofEarth, Ocean and Atmospheric Sciences, Department ofReviewedFacult

Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice

Abstract Background Disentangling the interplay between experience-based intuition and theory-informed implementation is crucial for identifying the direct contribution theory can make for generating behaviour changes needed for successful evidence translation. In the context of ‘clinicogenomics’, a complex and rapidly evolving field demanding swift practice change, we aimed to (a) describe a combined clinician intuition- and theory-driven method for identifying determinants of and strategies for implementing clinicogenomics, and (b) articulate a structured approach to standardise hypothesised behavioural pathways and make potential underlying theory explicit. Methods Interview data from 16 non-genetic medical specialists using genomics in practice identified three target behaviour areas across the testing process: (1) identifying patients, (2) test ordering and reporting, (3) communicating results. The Theoretical Domains Framework (TDF) was used to group barriers and facilitators to performing these actions. Barriers were grouped by distinct TDF domains, with ‘overarching’ TDF themes identified for overlapping barriers. Clinician intuitively-derived implementation strategies were matched with corresponding barriers, and retrospectively coded against behaviour change techniques (BCTs). Where no intuitive strategies were provided, theory-driven strategies were generated. An algorithm was developed and applied to articulate how implementation strategies address barriers to influence behaviour change. Results Across all target behaviour areas, 32 identified barriers were coded across seven distinct TDF domains and eight overarching TDF themes. Within the 29 intuitive strategies, 21 BCTs were represented and used on 49 occasions to address 23 barriers. On 10 (20%) of these occasions, existing empirical links were found between BCTs and corresponding distinct TDF-coded barriers. Twenty additional theory-driven implementation strategies (using 19 BCTs on 31 occasions) were developed to address nine remaining barriers. Conclusion Clinicians naturally generate their own solutions when implementing clinical interventions, and in this clinicogenomics example these intuitive strategies aligned with theoretical recommendations 20% of the time. We have matched intuitive strategies with theory-driven BCTs to make potential underlying theory explicit through proposed structured hypothesised causal pathways. Transparency and efficiency are enhanced, providing a novel method to identify determinants of implementation. Operationalising this approach to support the design of implementation strategies may optimise practice change in response to rapidly evolving scientific advances requiring swift translation into healthcare

Understanding the dual role of clinician-scientists in cancer clinical trials: a scoping review protocol

ABSTRACT Objectives: This scoping review explores healthcare professionals’ experiences delivering cancer-related clinical trials, including how ‘research’ and ‘clinical practice’ activities interact and/or interfere with trial delivery and patient care. Introduction: Clinical trial research is essential for advancing the quality of care delivered to cancer patients. Healthcare professionals are the main point of contact for patients participating in a trial and play a critical role in trial conception/design, recruitment, informed consent, intervention delivery, and/or monitoring patient outcomes, whilst concurrently providing good clinical practice. Barriers to undertaking trial research are well documented at patient- and systems-levels, yet little is known about how clinical trial research impacts healthcare professionals. Inclusion criteria: This review will consider articles that meet the following criteria: (1) includes any healthcare professional involved in the delivery of a cancer-related clinical trial, (2) concepts of interest include experiences, attitudes or perceptions reported by healthcare professionals pertaining to trial delivery, and (3) context is within or in relation to the hospital setting. Study sources must be published in a peer-reviewed journal from 2000-present and be English-based or translated. Methods: The search will be conducted in Embase (OVID) and PubMED (MEDLINE) databases. The lead reviewer will screen all articles, while a second reviewer will screen a selection (~20%) of titles/abstracts, and full texts. Study characteristics will be extracted using a data extraction table, and qualitative data will be thematically analysed (via NVivo 14) using a mixed inductive/deductive process informed by implementation science frameworks. Keywords: Clinical trials, oncology, implementation science, clinician-researcher, health-care deliver

Additional file 1 of Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice

Additional file 1. BCTTv1_PDF (behaviour change technique labels and definitions) [9]

Additional file 2 of Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice

Additional file 2. Genomics implementation barrier and strategy mapping and theory alignment (interview data coded to theoretical domains framework and behaviour change techniques, alignment of intuitive strategies against behaviour change techniques)

Additional file 4 of Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice

Additional file 4. TIDieR-Checklist_completed

Additional file 3 of Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice

Additional file 3. TDF domains and BCTs counting exercise (counts of number of barriers, TDF domains represented, behaviour change techniques used, theoretical alignment of intuitive strategies)

Whole-genome landscape of pancreatic neuroendocrine tumours

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling