The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is unknown. Here, we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets with strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+) tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens

Injury prevalence across sports: a descriptive analysis on a representative sample of the Danish population

Abstract Background Physical activity plays an important role in public health, owing to a range of health-related benefits that it provides. Sports-related injuries are known to be an important barrier to continued physical activity. Still, the prevalence of injuries on a general population level has not yet been explored in a descriptive epidemiological investigation. The purpose of the questionnaire-based study, therefore, was to describe the prevalence of injury in a representative sample of the Danish population. Methods Two samples of 10,000 adults (> 15 years) and 6500 children and adolescents (7–15 years) were invited to respond to a web-based questionnaire. Of these, 3498 adults (35.0%) and 3221 children (49.6%) responded successfully. The definition of sports injury was time-loss and medical attention-based, inhibiting participants from sports activity for at least 7 days, and/or involved contact with a healthcare professional, respectively. Results Amongst adults, 642 (18.4% [95%CI: 17.1%; 19.6%]) reported to have had an injury within the past 12 months. Males reported significantly more injuries than females (difference in prevalence proportion: 9.2%-points [95%CI: 6.7%-points; 11.8%-points]). The prevalence of injuries was greatest in running (ninj = 198), football (ninj = 94) and strength training (ninj = 89). Amongst children, 621 (19.3% [95%CI: 17.9%; 20.6%]) had been injured. No difference in injury prevalence proportion existed between boys and girls. The prevalence of injuries was greatest in football (ninj = 235), handball (ninj = 86) and gymnastics (ninj = 66). Conclusions Sports injuries seem to be very frequent in Denmark, since a total of 18.4% of the adults and 19.3% of the children reported having had one or more injuries within the past 12 months, equal to either time lost with physical activity and/or contact to the health care system

Time-to-event analysis for sports injury research part 1: time-varying exposures

BACKGROUND: 'How much change in training load is too much before injury is sustained, among different athletes?' is a key question in sports medicine and sports science. To address this question the investigator/practitioner must analyse exposure variables that change over time, such as change in training load. Very few studies have included time-varying exposures (eg, training load) and time-varying effect-measure modifiers (eg, previous injury, biomechanics, sleep/stress) when studying sports injury aetiology. AIM: To discuss advanced statistical methods suitable for the complex analysis of time-varying exposures such as changes in training load and injury-related outcomes. CONTENT: Time-varying exposures and time-varying effect-measure modifiers can be used in time-to-event models to investigate sport injury aetiology. We address four key-questions (i) Does time-to-event modelling allow change in training load to be included as a time-varying exposure for sport injury development? (ii) Why is time-to-event analysis superior to other analytical concepts when analysing training-load related data that changes status over time? (iii) How can researchers include change in training load in a time-to-event analysis? and, (iv) Are researchers able to include other time-varying variables into time-to-event analyses? We emphasise that cleaning datasets, setting up the data, performing analyses with time-varying variables and interpreting the results is time-consuming, and requires dedication. It may need you to ask for assistance from methodological peers as the analytical approaches presented this paper require specialist knowledge and well-honed statistical skills. CONCLUSION: To increase knowledge about the association between changes in training load and injury, we encourage sports injury researchers to collaborate with statisticians and/or methodological epidemiologists to carefully consider applying time-to-event models to prospective sports injury data. This will ensure appropriate interpretation of time-to-event data

The effect of speed on Achilles tendon forces and patellofemoral joint stresses in high‐performing endurance runners

Achilles tendinopathy and patellofemoral pain are common running injuries associated with increased Achilles tendon (AT) forces and patellofemoral joint (PFJ) stresses. This study examined AT forces and PFJ stresses at different running speeds in high performing endurance runners. Twenty runners ran overground at four running speeds (3.3, 3.9, 4.8 and 5.6m/s). AT forces and PFJ stresses were estimated from kinematic and kinetic data. Repeated measures ANOVA with partial eta squared effect sizes were conducted to assess differences between running speeds. Increased peak AT forces (19.5%; p<.001) and loading rates (57.3%; p<.001) from 3.3m/s to 5.6m/s were observed. Cumulative AT loading was greater in the faster speeds compared to the slower speeds. Faster running speeds resulted in increased peak plantar flexor moments, increased peak plantarflexion angles, and a more flexed knee and an anterior centre of pressure position at touchdown. Peak PFJ stress was lower in the slowest speed (3.3 m/s) compared to the faster running speeds (3.9‐5.6m/s; p=.005). PFJ stress loading rate significantly increased (43.6%; p<.001). Greater AT loading observed could be associated with strategies such as increased plantar flexor moments and altered lower body position at touchdown which are commonly employed to generate greater ground contact forces. Greater AT and PFJ loading rates were likely due to shorter ground contact times and therefore less time available to reach the peak. Running at faster speeds could increase the risk of developing Achilles tendinopathy and patellofemoral pain or limit recovery from these injuries without sufficient recovery

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC