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The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.

Hintergrund: Relativer Energiemangel (Relative Energy Deficiency in Sports, RED-S) kann sowohl Folge als auch Ursache einer psychischen Erkrankung sein. Im Gegensatz zu Essstörungen ist nur wenig über den Zusammenhang zwischen RED-S und Depressionen bekannt. Ziel dieser Untersuchung war zu überprüfen, ob depressive Symptome bei Ausdauersportlerinnen mit typischen Risikoindikatoren für RED-S einhergehen. Methoden: In einer Querschnittserhebung wurden 23 Ausdauerathletinnen (27 ± 6 Jahre, BMI 20,6 ± 2 kg/m²) untersucht. Das Risiko für RED-S wurde mittels des Low Energy Availability in Females Questionnaire (LEAF-Q) bewertet. Eine Absenkung des Ruheenergieumsatzes (RMR) und Trijodthyronin (T3) dienten als weitere objektive Indikatoren für das Vorliegen von RED-S. Der Patient Health Questionnaire-9 (PHQ-9) wurde zur Bewertung des Risikos von depressiven Symptomen und der Brief Eating Disorder in Athletes (BEDA-Q) zur Bewertung des Risikos von gestörtem Essverhalten verwendet. Ergebnisse: Anhand der LEAF Scores wiesen 52 % der Probandinnen ein erhöhtes Risiko für eine geringe Energieverfügbarkeit auf. Im Gegensatz zu Athletinnen mit einem geringen Score zeigten sich bei betroffenen Athletinnen erniedrigte T3-Werte (17 % vs. 9 %), ein reduzierter RMR (RMRRatio < 0.9;42 % vs. 36 %) sowie ein erhöhtes Risiko für ein gestörtes Essverhalten (42 % vs. 9 %) und depressive Symptome (83 % vs. 27 %). Bei 17 % der Probandinnen mit hohem LEAF Score handelte es sich um mittelgradige depressive Symptome, bei allen anderen Betroffenen waren diese leichter Ausprägung. Scores des PHQ-9 korrelierten mit denen des LEAF-Q (r = 0.614, p = 0.002). Schlussfolgerung: Die Untersuchung zeigt erstmals, dass Ausdauerathletinnen mit einem erhöhten Risiko für eine geringe Energieverfügbarkeit ein ebenfalls erhöhtes Risiko für depressive Symptome aufweisen. Die Direktionalität des Zusammenhangs zwischen depressiven Symptomen und RED-S ist in zukünftigen Studien zu klären.

Relative energy deficiency in sports (RED-S) is centered by chronic low energy availability (LEA), with a bidirectional causative relationship with mental health. Aside the well-established link between eating disorders and LEA, exercise addiction (ExA) has been proposed as another independent LEA risk factor. The aim of this investigation was to assess the relationship between LEA, eating disorders, ExA and biomarkers indicative of LEA in a sample of female endurance athletes. In a cross-sectional study, 23 athletes (27 ± 6 yrs, BMI 20.6 ± 2.0 kg/m2) who train ≥ 4 times/week completed the Low Energy in Females Questionnaire (LEAF-Q), the Brief Eating Disorder in Athletes Questionnaire (BEDA-Q), and an expanded version of the Exercise Addiction Inventory (EAI). Biomarkers of LEA included a reduction in resting metabolic rate, defined as a ratio of measured and predicted RMR < 0.9 and reduced circulating concentrations of triiodothyronine (T3). According to the LEAF scores, 52% of all athletes were at risk of LEA. Athletes at risk for LEA demonstrated a higher risk for eating disorders (42% vs. 9%) and exercise addiction (ExA; 25% vs. 0%), which was predominantly (67%) categorized as secondary ExA. Overall, EAI scores were increased in athletes at risk for LEA (22.4 ± 3.7 vs 18.9 ± 2.7, p=0.014), and more of those athletes reported to train despite pain or injury (42% vs. 18%). Additionally, athletes at risk for LEA were more likely to have suppressed RMR and low T3 (42% vs 36% and 17% vs. 9% respectively). EAI scores were not associated with LEA biomarkers. Our findings indicate that the inclusion of exercise addiction could complement the LEAF-Q when screening athletes for LEA. Given that mental health and LEA are bidirectional, early detection of compromised mental health could aid in prevention of chronic LEA and RED-S. Acknowledgements: This study was funded by the Robert-Enke-Foundation.

Die Triade der Sport treibenden Frau ist ein Symptomenkomplex aus Störungen des Essverhaltens, Störungen des Menstruationszyklus und Osteoporose. Das Syndrom des relativen Energiemangels im Sport (RED-S) schließt in Erweiterung der Triade alle Formen, auch die nicht eindeutig krankhaften, einer zu geringen Energiezufuhr ein. Für das „Return to Sport“ nach RED-S spielt die medizinische Trainingstherapie eine wichtige Rolle.

Alpine skiing is characterized by phases of demanding on-snow glacier training and competitions in extreme environments, where maintaining body composition (BC) is crucial for performance and may play a role in injury prevention. However, sport-specific literature on energy balance (EB) and strategies to avoid unfavorable changes in BC are still lacking. PURPOSE: To analyze EB and BC during a training camp at altitude and over the course of a competitive season. METHODS: In a prospective observational study, active male (n = 9, 27 ± 2.9 yrs) and female (n = 10, 25 ± 3.0 yrs) international skiers, competing in either speed (SPEED; n = 10) or technical (TEC; n = 9) disciplines, completed a 7 to 15-day training camp at altitude (base: 1800 m, glacier: 3500 m). BC (displacement plethysmography and bioelectrical impedance) was assessed at baseline, directly before and after the camp and at the end of the season. At altitude, food intake was assessed directly and indirectly, urine samples were collected for estimation of energy expenditure (doubly labelled water isotope method). RESULTS: During the training camp, an overall increase in body mass (BM, p = 0.011) and fat mass (FM, p < 0.001) was observed, whereas FFM remained unchanged. Increases in FM were prominent in men (p < 0.001) and SPEED (p = 0.002), but not in women or TEC. An average total daily energy expenditure (TEE) of 4088 ± 895 kcal/d and an energy intake (EI) of 4375 ± 1223 kcal resulted in an overall positive EB. EE in SPEED was significantly higher than in TEC (p = 0.03), with the highest EE observed in male speed athletes (~5900 kcal). Moreover, EB differed (p = 0.01) between men (760 ± 890 kcal/d) and women (-138 ± 490 kcal/d). Over the course of a season, FFM (p = 0.007) and skeletal muscle mass (SMM, p = 0.05) decreased significantly. Whereas women tended lose more SMM than men (p = 0.09), reductions in BM tended to be greater in male when compared to female athletes (p = 0.07). CONCLUSION: The findin

The competitive season in long-distance triathlon is characterized by increases in training load and volume from off- to peak-season, when athletes enter their primary competition. When athletes fail to meet the increased energy demand through the diet, either unintentionally or in attempts to improve their performance by means of weight loss, they are at an increased risk for low energy availability (LEA), which can negatively impact their health and performance. PURPOSE: To analyze changes in body composition over the course of the competitive season and investigate indicators of LEA in long-distance triathletes. METHODS: Study I consisted of a longitudinal analysis of changes in body composition (10-point skinfolds) over the course of a full competitive season in 29 triathletes (90% males, 44 ± 8 yrs, 75.9 ± 8.2 kg). Study II consisted of an analysis of surrogate markers of LEA in 13 triathletes (77% males, 36 ± 11 yrs, 73.3 ± 8.9 kg) and involved measures of resting metabolic rate (RMR) and triiodothyronine (T3). In male athletes, testosterone (TES) and reproductive function (Aging Males’ Symptoms scale; AMS) were analyzed additionally. All measurements in study II were conducted prior to the peak competition, the time point at which LEA risk was presumed to be highest. RESULTS: In study I, we observed significant reductions in body weight (−2.6 ± 3.8%), fat mass (−11.2 ± 14.9%), and fat-free mass (−1.2 ± 2.5%) from off- to peak-season (p < 0.05). Body composition returned to baseline at the end of the season. In study II, RMR was reduced (RMRratio < 0.9) in 2 athletes (15%). TES was below the clinical range in 1 athlete (10%) and in the lower quartile in 3 additional athletes (30%). TES was correlated with T3 (r = 0.77, p = 0.01), but neither TES nor T3 was correlated with RMRratio. Males with low TES had higher AMS scores than athletes with normal TES (9.25 ± 7.2 vs. 7.1 ± 3.0, p = 0.33). CONCLUSION: In triathlon, the competitive season is associated with weig