Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited. We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week−1 via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention’s effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFβ, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFβ, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes. The accrual target was met after screening 101 cases (enrollment rate: 39.6 %). Other outcomes included a retention rate of 85 %, excellent adherence (95 %), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were “too busy” (30 %), medical exclusions (21 %), and “distance” (16 %). Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets. NCT01886677

Introduction Obesity is a known risk factor for postmenopausal breast cancer and is associated with poorer prognosis for premenopausal and postmenopausal patients; however, the aetiological mechanisms are unknown. Preclinical studies support weight loss via caloric restriction and increased physical activity as a possible cancer control strategy, though few clinical studies have been conducted. We undertook a feasibility trial among women recently diagnosed with stage 0–II breast cancer hypothesising that presurgical weight loss would be feasible, safe and result in favourable changes in tumour markers and circulating biomarkers. Methods and analysis A two-arm randomised controlled trial among 40 overweight or obese women, newly diagnosed with stage 0–II breast cancer and scheduled for surgery was planned. The attention control arm received upper body progressive resistance training and diet counselling to correct deficiencies in nutrient intake; the experimental arm received the same plus counselling on caloric restriction and aerobic exercise to achieve a weight loss of 0.68–0.919 kg/week. In addition to achieving feasibility benchmarks (accruing and retaining at least 80% of participants, and observing no serious adverse effects attributable to the intervention), we will explore the potential impact of an acute state of negative energy balance on tumour proliferation rates (Ki-67), as well as other tumour markers, serum biomarkers, gene expression, microbiome profiles and other clinical outcomes (eg, quality of life). Outcomes for the 2 study arms are compared using mixed models repeated-measures analyses. Ethics and dissemination Ethics approval was received from the University of Alabama at Birmingham Institutional Review Board (Protocol number F130325009). Study findings will be disseminated through peer-reviewed publications. Given that this is one of the first studies to investigate the impact of negative energy balance directly on tumour biology in humans, larger trials will be pursued if results are favourable. Trial registration number NCT02224807; Pre-results.

Background: Although ultraviolet B (UVB) radiation-induced immunosuppression is considered a key risk factor for skin cancer, individual susceptibility varies, and its mechanisms remain not fully understood. Objective: The current study collected skin biopsies from healthy volunteers before and after UVB radiation and linked UVB-induced effects in the skin to immunosuppression in the same individuals. Methods: A total of 62 healthy volunteers were recruited and randomly assigned to three groups: negative, positive, and UVB-exposed. Diphenylcyclopropenone was applied topically to induce contact hypersensitivity (CHS) responses. Skin punch biopsies were collected before and after UVB for analysis. Results: UVB exposure significantly suppressed CHS compared to the positive control. However, among 26 individuals, 7 (27%) were resistant (UVB-R), while the rest were susceptible (UVB-S) to UVB-induced immunosuppression. RNA-seq analysis of skin biopsies showed that UVB induced a higher level of immunosuppressive inflammation in UVB-S than in UVB-R individuals. Further analysis showed that UVB significantly activated the damage-associated molecular patterns only in UVB-S, but not in UVB-R individuals. Conclusion: Given the role of DAMP pathways in the development of inflammation, the results reveal a previously unrecognized mechanism: UVB-induced activation of DAMP pathways is linked to UVB-induced immunosuppressive inflammation in skin and susceptibility to immunosuppression in humans.

Background: Immune checkpoint inhibitors and adoptive T-cell therapies have substantially improved cancer treatment outcomes, but their use is often limited by immune-related toxicities, including cytokine release syndrome. The role of interleukin (IL)-17A in tumor immunity remains controversial, hindering its therapeutic applications in cancer. A concern is that application of IL-17 blocking agents to release cytokine storms caused by tumor immunotherapy reverses anti-tumor immunity. Methods: In this study, we evaluated the effect of IL-17A blockade alone and in combination with anti–PD (programmed cell death)-1 therapy or tumor-specific CD8⁺ T cells in melanoma, colon, and lung tumors, and in UVB-induced skin carcinogenesis. Results: Our results showed that blocking IL-17A inhibited tumor development, and did not impair the efficacy of tumor immunotherapies with checkpoint inhibitors or tumor-specific T cells. Combined treatment with anti-IL-17A and anti-PD-1 antibodies significantly enhanced tumor suppression compared to single-agent therapies in all tested tumor models. Moreover, IL-17A blockade improved the efficacy of adoptive CD8⁺ T-cell therapy. Mechanistic analyses revealed that the combination therapy increased infiltration of activated antigen-specific CD8⁺ T cells in tumors. In none of the tested tumor models did IL-17A blockade negatively affect the efficacy of tumor immunotherapy with checkpoint inhibitors or T-cell therapy. Conclusions: These findings suggest that the combined application of anti-IL-17A blocking agents with current tumor immunotherapy at the same time is a promising strategy to enhance the efficacy and potentially diminish immune-related adverse effects.