Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

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.

Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer.

Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled. Mouse models of pancreatic cancer recapitulate the immune-microbial spatial coupling seen in humans. Distinct intra-tumoral niches are defined by T cells, with T cell-enriched and T cell-poor regions displaying unique bacterial communities that are associated with immunologically active and quiescent phenotypes, respectively, but are independent of the gut microbiome. Depletion of intra-tumoral bacteria slows tumor growth in T cell-poor tumors and alters the phenotype and presence of myeloid and B cells in T cell-enriched tumors but does not affect T cell infiltration. In contrast, T cell depletion disrupts the immunological state of tumors and reduces intra-tumoral bacteria. Our results establish a coupling between microbes and T cells in cancer wherein spatially defined immune-microbial communities differentially influence tumor biology.

Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1.

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

First, do no harm: why anti-immigrant policies in the United States are a public health concern.

It can be argued that anti-immigrant policies, such as the 287(g) program, can have a direct impact on the health and well-being of the immigrant community in general, particularly undocumented immigrants in the United States. While there is yet to be a comprehensive and conclusive empirical assessment of this issue, what is known is that the immigrant community faces many stress factors and structural barriers that negatively impact health. We argue that it is urgent that public health responds to the unique experiences and challenges of the undocumented and wider immigrant community. In doing so, we propose three recommendations for addressing this issue: (1) Assess the causal relationship between anti-immigration policies and immigrant health, (2) Increase funding and access to health care services for immigrant communities in jurisdictions implementing anti-immigrant policies, and (3) For public health to engage in a conscious effort to service the undocumented immigrant community. Even though we focus specifically on the United States, our recommendations are applicable on a global scale since anti-immigration policies are prevalent across nations and are a pervasive human rights issue around the world.

Risk and protective factors related to alcohol and drug use amongst American Indian youth: An application of the social development model.

The goal of this study is to assess the relevance of the Social Development Model (SDM) in predicting substance use across American Indian (AI) youth. We rely on self-reported data collected as part of the 2004 Arizona Youth Survey (AYS). The final sample included 2,912 AI students from 169 schools in 15 counties. Results indicate relatively high levels of alcohol and drug use amongst AI youth. Overall, we find the SDM as a promising framework for identifying risk factors associated with the increased likelihood of alcohol and drug use amongst AI youth.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients.

Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.

A study of firesetting and animal cruelty in children: family influences and adolescent outcomes.

OBJECTIVE: To investigate relationships among family risk factors, childhood firesetting and animal cruelty, and adolescent delinquency. METHOD: In 1990, mothers and children participating in a 10-year prospective study provided information about family risk factors and childhood problem behavior. Subsequent interviews with 86% of the sample in 1996 and 1998 and court record reviews in 2000 provided information about juvenile delinquency. RESULTS: Marital violence (odds ratio [OR] 2.4, 95% confidence interval [CI] = 1.1-5.4), paternal pet abuse (OR 2.4, CI = 1.0-5.6), and paternal drinking (r = 0.14) were related to firesetting, whereas exposure to marital violence (OR 2.3, CI = 1.0-5.1) and paternal (r = 0.19) and maternal harsh parenting (r = 0.14) were associated with animal cruelty. Regression analyses indicated that after controlling for conduct disorder, firesetters were 3.0 times (CI = 1.3-6.7) at risk of juvenile court referral and 3.3 times (CI = 1.4-7.6) at risk of arrest for a violent crime. Analysis of self-reports of delinquency replicated these results. Animal cruelty was related to self-reported violent crime (beta = 0.16). CONCLUSION: These findings indicate that family variables increase the likelihood of childhood firesetting and animal cruelty and that these behaviors are related to adolescent delinquency.

Sexual abuse, family violence, and female delinquency: findings from a longitudinal study.

The current study examines the effects of three forms of childhood victimization on self-reported delinquency and aggression in adolescent girls. These analyses are based on a longitudinal sample of 141 mother-daughter pairs participating in a study about marital violence and child development. When the children were school aged, mothers and children provided reports describing (a) child exposure to marital violence, (b) escalated physical abuse against the child, and (c) child sexual abuse. Children were followed up into adolescence and re-interviewed. Self-reports of delinquency (violent and nonviolent), running away, and violence against parents were collected. Results indicate that out of the three forms of victimization, child sexual abuse emerged as the strongest predictor of girls' violent and nonviolent criminal behavior. Girls with a history of physical abuse in childhood were most likely to assault their parents. Witnessing marital violence failed to contribute further to delinquency, beyond the adverse association with childhood sexual abuse. Findings highlight a unique avenue for delinquency in girls via childhood sexual exploitation.