Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses.

Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.

A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) not only disrupt tumor angiogenesis but also have many unexpected side effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ("senomimetic") VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. By using a live cell sorting method to detect ß-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened IFN signaling and increased expression of IFN-stimulated genes (ISGs). These ISGs increase under the control of the STimulator of the INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host-tumor cell contact while tumors grown from SM+ cells were more sensitive to PDL1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side effects may help identify TKIs that uniquely "prime" tumors for enhanced sensitivity to PDL1-targeted agents.

A senescence-mimicking (senomimetic) VEGFR TKI side-effect primes tumor immune responses via IFN/STING signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ('senomimetic') VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. Using a live-cell sorting method to detect beta-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened interferon (IFN) signaling and increased expression of IFN-stimulated genes (ISGs). These ISG increases were under the control of the STimulator of INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host:tumor cell contact while tumors grown from SM+ cells were more sensitive to PD-L1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side-effects may help identify TKIs that uniquely 'prime' tumors for enhanced sensitivity to PD-L1 targeted agents.

Untreated Psychiatric and Substance Use Disorders Among Caregivers With Children Reported to Child Protective Services.

Importance: Mental and substance use disorders can interfere with parents' ability to care for their children and are associated with a greater likelihood of child protective services involvement to address child maltreatment. Parent engagement in psychiatric and substance use disorder treatment can prevent child maltreatment and family separations. Objective: To determine whether caregivers with psychiatric or substance use disorders whose children were referred to child protective services received Medicaid-funded psychiatric or substance use disorder treatment. Design, Setting, and Participants: Caregivers listed on child welfare records were linked with their Medicaid records using 2017 to 2020 Medicaid and child welfare data from Florida and Kentucky. Medicaid claims were analyzed to determine if caregivers had a psychiatric or substance use disorder diagnosis and whether those caregivers received counseling or medications. The analysis was conducted in 2023. Exposure: Diagnosis of a psychiatric or substance use disorder in 2020. Main Outcome and Measure: Receipt of psychiatric or substance use disorder counseling or medications. Results: Of the 58 551 caregivers, 65% were aged between 26 and 40 years; 69% were female and 31% were male. Overall, 78% identified as White, 20% identified as Black/African American, and less than 1% identified as American Indian/Alaska Native, Asian, or Native Hawaiian/Other Pacific Islander. In 2020, 59% of caregivers with Medicaid and children referred to child protective services had a mental health or substance use disorder diagnosis, compared with 33% of age- and sex-matched Medicaid beneficiaries without children referred to child protective services (P < .001). Among caregivers with a psychiatric disorder, 38% received counseling and 67% received psychiatric medication. Among those with a substance use disorder, 40% received counseling and 38% received a substance use disorder medication. Conclusions and Relevance: In this case-control study, despite Medicaid coverage of an array of effective behavioral health treatments, large portions of caregivers with Medicaid coverage, who need treatment and whose children were referred to child protective services, were not receiving treatment. Medicaid and child welfare agencies should make a greater effort to connect caregivers to behavioral health services.

Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression.

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.

Linked Child Welfare and Medicaid Data in Kentucky and Florida Highlights Racial Disparities in Access to Care.

Parents with serious mental health (MH) and substance use disorders (SUD) can face profound challenges caring for their children. MH/SUD treatment can improve outcomes for both parents and their children. This study evaluated whether parents with Medicaid with MH/SUD conditions whose children had child protective services (CPS) involvement were receiving MH/SUD treatment and whether receipt differed by race. We analyzed the 2020 Child and Caregiver Outcomes Using Linked Data (CCOULD) which contains Medicaid and child welfare records from Kentucky and Florida on 58,551 CPS-involved caregivers. Among caregivers with an MH diagnosis, White individuals were more likely than Black individuals to have received counseling (42% vs. 20%) or an MH medication (69% vs. 52%). Among caregivers with an SUD, White individuals were more likely than Black individuals to have received counseling (43% vs. 20%) or an SUD medication (43% vs. 11%). More effort is needed to connect parents with CPS involvement to MH/SUD treatment, particularly Black parents.

Immunization with short peptide particles reveals a functional CD8+ T-cell neoepitope in a murine renal carcinoma model.

BACKGROUND: Induction of CD8+ T cells that recognize immunogenic, mutated protein fragments in the context of major histocompatibility class I (MHC-I) is a pressing challenge for cancer vaccine development. METHODS: Using the commonly used murine renal adenocarcinoma RENCA cancer model, MHC-I restricted neoepitopes are predicted following next-generation sequencing. Candidate neoepitopes are screened in mice using a potent cancer vaccine adjuvant system that converts short peptides into immunogenic nanoparticles. An identified functional neoepitope vaccine is then tested in various therapeutic experimental tumor settings. RESULTS: Conversion of 20 short MHC-I restricted neoepitope candidates into immunogenic nanoparticles results in antitumor responses with multivalent vaccination. Only a single neoepitope candidate, Nesprin-2 L4492R (Nes2LR), induced functional responses but still did so when included within 20-plex or 60-plex particles. Immunization with the short Nes2LR neoepitope with the immunogenic particle-inducing vaccine adjuvant prevented tumor growth at doses multiple orders of magnitude less than with other vaccine adjuvants, which were ineffective. Nes2LR vaccination inhibited or eradicated disease in subcutaneous, experimental lung metastasis and orthotopic tumor models, synergizing with immune checkpoint blockade. CONCLUSION: These findings establish the feasibility of using short, MHC-I-restricted neoepitopes for straightforward immunization with multivalent or validated neoepitopes to induce cytotoxic CD8+ T cells. Furthermore, the Nes2LR neoepitope could be useful for preclinical studies involving renal cell carcinoma immunotherapy.

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance.

Tyrosine kinase inhibitors (TKIs) that primarily target angiogenesis are approved to treat several cancers in the metastatic setting; however, resistance is common. Sequential treatment or 'switching' from one TKI to another following failure can be effective, but predicting which drugs will have cross-over sensitivity remains a challenge. Here we examined sitravatinib (MGCD516), a spectrum-selective TKI able to block MET, TAM (TYRO3, AXL, MerTK) and multiple receptor families (including PDGFRs, VEGFRs, and Ephs). Transcriptomic analysis of several mouse and human cell lines revealed diverse molecular changes after resistance to two TKIs (sunitinib and axitinib) with multiple sitravatinib targets found to be upregulated. Sitravatinib treatment in vitro resulted in enhanced anti-proliferative effects in resistant cells and was improved compared to TKIs with similar target profiles. In vivo, primary tumor growth inhibition after sitravatinib treatment in mice was enhanced in resistant tumors and metastasis suppression improved when tumors were surgically removed. Together, these results suggest that the diverse and often inconsistent compensatory signaling mechanisms found to contribute to TKI resistance may paradoxically improve the tumor-inhibiting effects of broad-spectrum TKIs such as sitravatinib that are able to block multiple signaling pathways. Sitravatinib in the second-line setting following antiangiogenic TKI treatment may have enhanced inhibitory effects in local and disseminated disease, and improve outcomes in patients with refractory disease.

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal.

VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies ("senotherapeutics")-particularly those that block SASP regulation-may improve outcomes in patients after VEGFR TKI failure.

Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors.

The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor "host" treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral "side effects" of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare "off-target" host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or "therasomes") may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602-12. ©2018 AACR.

Families in need of domestic violence services reported to the child welfare system: Changes in the National Survey of Child and Adolescent Well-Being between 1999-2000 and 2008-2009.

This study aimed to determine if identification of intimate partner violence (IPV) has improved by caseworkers that investigate reports of child maltreatment and if mothers who are victims of IPV are more likely to report receipt of services. The study data were drawn from the two cohorts of the National Survey of Child and Adolescent Well-Being (NSCAW I and II), the first in 1999-2000 with a sample of 5,501 children reported for maltreatment and the second in 2008-2009 with a sample of 5,872 children reported for maltreatment. The analyses focused on IPV victimization of 3,625 mothers in NSCAW I and 3,351 mothers in NSCAW II whose children remained in home after the maltreatment investigation. Multiple group logistic regression was used to compare NSCAW I and II. A significant decrease in mother-reported IPV victimization (28.9-24.7%) was observed, representing a 15% decline. There were no significant changes in caseworker identification of history of domestic violence or active domestic violence. In both cohorts, substance abuse by the secondary caregiver was associated with a lower likelihood for the caseworker to miss a history of active domestic violence, while substantiation reduced the likelihood that the caseworker will miss active domestic violence. There were no changes in caseworkers' service referral, or service receipt among victims. The next decade of efforts to reduce IPV and child maltreatment should focus simultaneously on increasing caseworkers' ability to identify IPV and on funding needed services for families impacted by IPV and child maltreatment.

Caregiver instability and early life changes among infants reported to the child welfare system.

This study describes the extent of caregiver instability (defined as a new placement for 1 week or longer in a different household and/or with a new caregiver) in a nationally representative sample of infants, followed for 5-7 years. Data were drawn from the National Survey of Child and Adolescent Well-Being (NSCAW), a longitudinal study of 5,501 children investigated for child maltreatment. The analysis sample was restricted to 1,196 infants. Overall, 85.6% of children who were infants at the time of the index maltreatment experienced at least one caregiver instability event during their first 2 years of life. Caregiver instability was associated with the child having a chronic health condition and the caregiver being older than 40 years of age at baseline. The levels of instability reported in this study from infancy to school entry are extremely high. Children with more risk factors were significantly more likely to experience caregiver instability than children with fewer risk factors. The repeated loss of a young child's primary caregiver or unavailable, neglectful care can be experienced as traumatic. Some evidence-based programs that are designed to work with young maltreated children can make a substantial positive difference in the lives of vulnerable infants.

An efficiency-based multicriteria strategic planning model for ambulatory surgery centers.

Ambulatory surgery centers (ASCs) provide a low-cost alternative to traditional inpatient care. In addition, with health care reform imminent, it is likely that many currently uninsured people will soon acquire health care coverage, significantly increasing the demand for health services. ASCs are among the providers that can expect to see a substantial amount of this new pent-up demand and, therefore, ASCs are likely to continue their current growth into the foreseeable future. Those ASCs that plan accordingly by optimizing procedure mix and volume will benefit most from the increased demand. We propose a two-stage efficiency-based multicriteria decision model to guide an ASC in identifying its optimal procedure mix. The first stage uses Data Envelopment Analysis (DEA) to calculate the efficiency of each procedure based on the resources required to perform the procedure, the revenue it generates, and its risk of complications. The second stage uses the DEA factor efficiency scores in a bottleneck program to optimize the mix of procedures while satisfying the ASC's resource and operational constraints. The criteria are to (1) maximize reimbursement while (2) minimizing the total number of complications. We demonstrate the approach using a data set based in part on data from an actual ASC.

Amount of social contact and hip fracture mortality.

OBJECTIVES: To study the association between amount of social contact and mortality after hip fracture in elderly participants. DESIGN: Prospective cohort. SETTING: Community residents of Baltimore, Maryland. PARTICIPANTS: Six hundred seventy-four elderly participants. MEASUREMENTS: Amount of telephone and direct personal contact between participants and their relatives and friends and mortality up to 2 years after fracture. RESULTS: No social contact with friends during the 2 weeks before the fracture was associated with a five times greater risk of death over 2 years than daily contact with friends during the 2 weeks before the fracture (hazard ratio (HR)=5.04, 95% confidence interval (CI)=2.75-9.23). Participants with less than daily contact were also at greater risk of dying, although the CI spanned 1 (HR=1.76, 95% CI=0.99-3.13). Participants who had no contact with family members prefracture were more than twice as likely to die as those who communicated daily during the 2 weeks before fracture (HR=2.26, 95% CI=1.36-3.77). Participants who had less than daily contact were also more than twice as likely to die (HR=2.55, 95% CI=1.65-3.94). CONCLUSION: This study suggests that lower social contact before hip fracture is associated with poorer survival after 2 years.

Measuring and maximizing coverage in the World Trade Center Health Registry.

The World Trade Center Health Registry (WTCHR) is a database for following people who were exposed to the disaster of 11 September 2001. Hundreds of thousands of people were exposed to the immense cloud of dust and debris, the indoor dust, the fumes from persistent fires, and the mental trauma of the terrorist attacks on the WTC on 9/11. The purpose of the WTCHR is to evaluate the potential short- and long-term physical and mental health effects of the disaster. The definitions of the exposed groups are broad and defined based on an understanding of which groups had the highest exposures to the WTC disaster and its aftermath. The four exposure groups include rescue and recovery workers, residents, students and school staff, and building occupants and passersby in Lower Manhattan. While one goal of the WTCHR was to maximize coverage overall and for each exposure group, another was to ensure equal representation within exposure groups. Because of the multiple sample types pursued, several approaches were required to determine eligibility. Estimates of the number of eligible persons in each of the exposed populations were based on the best available information including Census, entity-specific employment figures, and public and private school enrollment data, among other publicly available sources. To address issues of undercoverage and overcoverage a variety of methods were assessed or applied, including a capture-recapture analyses test of overlapping sample building list sources and automated deduplication of sample records. Estimates of the true eligible population indicate that over 400,000 unique individuals were eligible for the baseline health survey. Interviewer-administered surveys were completed with more than 71,000 persons, resulting in an overall enrollment rate of approximately 17 per cent. Coverage was highest among rescue and recovery workers, followed by residents, students and school staff, and building occupants. Both the accuracy of coverage estimates and the raw number and representativeness of enrollees were maximized by our approach to coverage. In designing a registry which relies on multiple pathways and sources of data to build the sample, it is important to develop a comprehensive approach that considers all sources of error and minimizes bias that may be introduced through the methodology.

Cognitive impairment in hip fracture patients: timing of detection and longitudinal follow-up.

OBJECTIVES: To examine the prevalence, incidence, persistence, predictors, and outcomes of cognitive impairment after hip fracture. DESIGN: Longitudinal cohort study. SETTING: Eight hospitals in Baltimore, Maryland. PARTICIPANTS: Six hundred seventy-four hip fracture patients aged 65 and older living in the community before fracture. MEASUREMENT: Delirium at admission and postsurgery, Mini-Mental State Examination (MMSE) scores postsurgery, and prefracture proxy ratings of MMSE and dementia. Follow-up measures at 2 and 12 months postfracture included mortality, MMSE, physical activities of daily living (PADLs), instrumental activities of daily living (IADLs), social functioning, and the Center for Epidemiologic Studies-Depression Scale. RESULTS: Overall, 28% had prefracture dementia or MMSE impairment, 8% had cognitive impairment first detected presurgery, 14% had impairment first detected postsurgery, and 50% were not impaired before or during hospitalization. Incident cognitive impairment was more likely in patients who were older, male, and less educated and had more prefracture PADL impairment, intertrochanteric fractures, and higher anesthesia risk ratings. Presurgery incident cases did not differ significantly from those detected postsurgery in functional outcomes or in persistence of cognitive impairment. Cognitive impairment first noted in the hospital persisted through 2 and 12 months in more than 40% of patients. Those with cognitive impairment persisting through 2 months had poorer 12-month PADLs and social functioning. CONCLUSION: Prefracture cognitive impairment and incident cognitive impairment during hospitalization are risk factors for poor functional outcomes. Many incident cognitive problems persisted over 2 to 12 months, and per-sistence predicted later functional and social impairment.