Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. ...Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both
and
. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1-blocking antibody in association with increased tumoral CD8
T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer. SIGNIFICANCE: This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti-PD-L1 therapy.
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The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic ...impacts of integrating genomic sequencing into the care of healthy and sick newborns.
Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns.
The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns.
The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.
Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during ...immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.
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•Hyperprogressive disease (HPD) occurs during immunotherapy•HPD is associated with high levels of IFNγ, FGF2, and β-catenin signaling•CD8+ T cell derived IFNγ promotes HPD via rewiring cancer oncometabolic pathways•High IFNγ-FGF2-β-catenin signature is a potential biomarker and target for HPD
Li et al. uncover crosstalk between core immunogenic, metabolic, and oncogenic pathways in cancer cells during immunotherapy, which enables hyperprogressive disease (HPD) in preclinical models and correlates with immunotherapy-associated HPD in patients with cancer.
Emotional eating, or eating in response to negative emotions rather than internal hunger cues, has been related to many maladaptive eating patterns that contribute to weight gain and obesity. The ...parent feeding practice of use of food as a reward is positively associated with children emotionally overeating, yet, little is known as to the potential behavioral mechanism linking these behaviors. The current study examined the mediating role of child self-regulation of eating in the relationship between parental use of food as a reward and child emotional overeating. Parents of preschool aged children (n = 254) completed online questionnaires targeting parent feeding practices, child eating behaviors, and child self-regulation in eating. Mediation was assessed with Hayes' PROCESS macros in SPSS. Results demonstrated that the relationship between parental use of food as a reward and child emotional overeating was partially mediated by child self-regulation in eating, even after controlling for parent and child gender, household income, and race/ethnicity. In summary, parental use of food as a reward leads to children's diminished ability to regulate intake, which then leads to increased emotional over eating. Results of this study have implications for both the prevention of disordered eating behaviors and childhood obesity prevention programs, suggesting the need to assist children in learning how to self-regulate in the presence of food.
Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader ...and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants’ known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant’s known clinical or family history, and the interpretation of results can substantially benefit from parental testing.
The present study examines the hypothesis that adult attachment orientation, specifically anxious attachment, is related to children's diminished ability to self-regulate their food intake, and that ...this relationship is mediated by parents' persuasive-controlling feeding practices. Two hundred and sixty five mothers and fathers of preschool children completed online questionnaires that included measures of Adult Attachment Orientation, Parental Persuasive-Controlling Feeding Practices, and Child Self-Regulation of Eating. Structural equation modeling revealed a significant relationship between parental anxious attachment and child self-regulatory abilities, which was fully mediated by parental persuasive-controlling feeding. Also as predicted, parents' avoidant attachment was found to be unrelated to persuasive-controlling feeding and child self-regulated eating. Findings suggest that parents with an anxious attachment orientation may be more likely than other parents to try to use persuasive techniques to control their children's food intake, which may impair children's ability to regulate their food intake, increasing their obesity risk. Implications for intervention are discussed.
•Parent attachment orientation impacts feeding practices and child eating.•Parent attachment anxiety is related to lower child self-regulation in eating.•That relationship is fully mediated by use of persuasive-controlling feeding practices.•Anxiously attached parents use persuasive-controlling feeding practices.
IMPORTANCE: Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on ...families. OBJECTIVE: To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. INTERVENTION: Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). MAIN OUTCOMES AND MEASURES: Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents’ relationship (Kansas Marital Satisfaction Scale), and parents’ psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). RESULTS: A total of 519 parents (275 women 53.0%; mean SD age, 35.1 4.5 years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean SE Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 0.15; 3 months, –0.18 0.18; 10 months, –0.07 0.20; joint P = .57) or parents’ psychological distress (between-group ratio of adjusted mean SE Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 0.08; 3 months, 1.07 0.11; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents’ relationship measure differed between groups over time (between-group difference in adjusted mean SE Kansas Marital Satisfaction Scale scores: postdisclosure, –0.19 0.07; 3 months, –0.04 0.07; and 10 months, –0.01 0.08; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02422511
Targeting the DNA damage response in combination with radiation enhances type I interferon (T1IFN)-driven innate immune signaling. It is not understood, however, whether DNA-dependent protein kinase ...(DNA-PK), the kinase critical for repairing the majority of radiation-induced DNA double-strand breaks in cancer cells, is immunomodulatory. We show that combining radiation with DNA-PK inhibition increases cytosolic double-stranded DNA and tumoral T1IFN signaling in a cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-independent, but an RNA polymerase III (POL III), retinoic acid-inducible gene I (RIG-I), and antiviral-signaling protein (MAVS)-dependent manner. Although DNA-PK inhibition and radiation also promote programmed death-ligand 1 (PD-L1) expression, the use of anti-PD-L1 in combination with radiation and DNA-PK inhibitor potentiates antitumor immunity in pancreatic cancer models. Our findings demonstrate a novel mechanism for the antitumoral immune effects of DNA-PK inhibitor and radiation that leads to increased sensitivity to anti-PD-L1 in poorly immunogenic pancreatic cancers.
Our work nominates a novel therapeutic strategy as well as its cellular mechanisms pertinent for future clinical trials combining M3814, radiation, and anti-PD-L1 antibody in patients with pancreatic cancer.
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