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Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver. The liver is the most common site of metastasis for pancreatic ductal adenocarcinoma (PDAC). Here, the authors demonstrate that β-glucan, a microbial component associated with trained immunity, activates liver-resident macrophages (Kupffer cells) and prevents PDAC metastasis to the liver

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA -mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA -mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, there is a lack of robust models that recapitulate the tumor microenvironment of BRCA mutated PDAC, limiting the development of next-generation maintenance treatment options. In this study, we developed a syngeneic and immunocompetent mouse model of Brca2 -mutated PDAC. The model demonstrated high sensitivity to cisplatin plus gemcitabine, but limited efficacy of PARPi monotherapy. Induction with platinum-based chemotherapy sensitized tumors to PARPi maintenance therapy and promoted an exhausted, T cell-inflamed tumor microenvironment. However, resistance emerged which was associated with CDX2 expression and tumor differentiation. The addition of anti-PD1 treatment to PARPi maintenance enhanced tumor regression and prolonged overall survival. These findings provide preclinical support for ongoing clinical trials investigating immunotherapy with PARPi as a maintenance strategy in homologous recombination-deficient PDAC.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8 + T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer. Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.

Pancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying Toll-like receptor 2 (TLR2) as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic knockout models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.

By the time I cleaned up, I noticed the \"it-wouldn't-be- Thanksgiving-without-it\" turkey had barely been touched. Maybe Thanksgiving could be Thanksgiving without turkey as the main course after all. And maybe, just maybe, my family and friends didn't really care. Makes 8-10 servings. To make this dish vegan, use olive oil instead of butter. To use it as part of a traditional Thanksgiving, bake it inside your turkey: Loosely fill main cavity with cool stuffing. Butter glass baking dish. Spoon remaining stuffing into prepared dish. Cover with buttered foil, buttered side down. Bake stuffing in dish alongside turkey until heated through, about 20 minutes. Adapted from Bon Appetit. Blanch onions in boiling water 1 minute; peel and set aside. In large skillet over medium heat, melt 2 tablespoons butter. Add onions and saute until brown, about 15 minutes. Set aside. In large saucepan, bring broth and 1 tablespoon chopped thyme to boil. Add wild rice (about 6 1/2 ounces); bring to boil. Reduce heat; cover and simmer 30 minutes. Add white rice; cover and simmer until all rice is tender and liquid is almost absorbed, about 15 minutes longer. Stir dried apricots (coarsely chopped), dried cherries, raisins and 2 tablespoons thyme into rice mixture; cover and simmer 3 minutes. Stir pearl onions and remaining 4 tablespoons butter into rice. Mix in chopped pecans. Season with salt and freshly ground pepper. Heat oven to 350 degrees. Butter 13x9x2-inch glass baking dish. Transfer stuffing to prepared dish. Cover with buttered foil, buttered side down; bake until heated through, about 30 minutes.

Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m2) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9·0 mg/kg every 3 weeks plus cisplatin 75 mg/m2) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54–78) in the chemoradiotherapy group and 61% (50–71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3–4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. Amgen.

HIV-positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare. This problem is acute in sub-Saharan Africa, where the world's majority of HIV-positive women live and prevalence of GBV is high. We conducted a randomized controlled trial at an HIV clinic in Kisumu, Kenya. GBV-affected HIV-positive women with both major depressive disorder (MDD) and PTSD were randomized to 12 sessions of interpersonal psychotherapy (IPT) plus treatment as usual (TAU) or Wait List+TAU. Nonspecialists were trained to deliver IPT inside the clinic. After 3 months, participants were reassessed, and those assigned to Wait List+TAU were given IPT. The primary outcomes were diagnosis of MDD and PTSD (Mini International Neuropsychiatric Interview) at 3 months. Secondary outcomes included symptom measures of depression and PTSD, intimate partner violence (IPV), and disability. A total of 256 participants enrolled between May 2015 and July 2016. At baseline, the mean age of the women in this study was 37 years; 61% reported physical IPV in the past week; 91% reported 2 or more lifetime traumatic events and monthly income was 18USD. Multilevel mixed-effects logistic regression showed that participants randomized to IPT+TAU had lower odds of MDD (odds ratio [OR] 0.26, 95% CI [0.11 to 0.60], p = 0.002) and lower odds of PTSD (OR 0.35, [0.14 to 0.86], p = 0.02) than controls. IPT+TAU participants had lower odds of MDD-PTSD comorbidity than controls (OR 0.36, 95% CI [0.15 to 0.90], p = 0.03). Linear mixed models were used to assess secondary outcomes: IPT+TAU participants had reduced disability (-6.9 [-12.2, -1.5], p = 0.01), and nonsignificantly reduced work absenteeism (-3.35 [-6.83, 0.14], p = 0.06); partnered IPT+TAU participants had a reduction of IPV (-2.79 [-5.42, -0.16], p = 0.04). Gains were maintained across 6-month follow-up. Treatment group differences were observed only at month 3, the time point at which the groups differed in IPT status (before cross over). Study limitations included 35% attrition inclusive of follow-up assessments, generalizability to populations not in HIV care, and data not collected on TAU resources accessed. IPT for MDD and PTSD delivered by nonspecialists in the context of HIV care yielded significant improvements in HIV-positive women's mental health, functioning, and GBV (IPV) exposure, compared to controls. Clinical Trials Identifier NCT02320799.

ObjectiveTo identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett’s oesophagus (BE).DesignWe performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.ResultsWe identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student’s t-test) and the highest global mutation load (p<0.05, Fisher’s exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch’s t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.ConclusionsWe identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

The U.S. federal Earned Income Tax Credit (EITC) is often considered the most effective antipoverty program for families in the U.S., leading to a variety of improved outcomes such as educational attainment, work incentives, economic activity, income, and health benefits for mothers, infants and children. State EITC supplements to the federal credit can significantly enhance the magnitude of this intervention. In this paper we advance EITC and health research by: 1) describing the diffusion of state EITC policies over 40 years, 2) presenting patterns in important EITC policy dimensions across space and time, and 3) disseminating a robust data set to advance future research by policy analysts and scientists. We used current public health law research methods to systematically collect, conduct textual legal analysis, and numerically code all EITC legislative changes from 1980 through 2020 in the 50 states and Washington, D.C. First, the pattern of diffusion across states and time shows initial introductions during the 1990s in the Midwest, then spreading to the Northeast, with more recent expansions in the West and South. Second, differences by state and time of important policy dimensions are evident, including size of credit and refundability. Third, state EITC benefits vary considerably by household structure. Continued research on health outcomes is warranted to capture the full range of potential beneficial effects of EITCs on family and child wellbeing. Lawyers and policy analysts can collaborate with epidemiologists and economists on other high-quality empirical studies to assess the many dimensions of policy and law that potentially affect the social determinants of health.