Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response.

Macroautophagy (hereafter autophagy) degrades and recycles intracellular components to sustain metabolism and survival during starvation. Host autophagy promotes tumor growth by providing essential tumor nutrients. Autophagy also regulates immune cell homeostasis and function and suppresses inflammation. Although host autophagy does not promote a T-cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that autophagy, especially in the liver, promotes tumor immune tolerance by enabling regulatory T-cell function and limiting stimulator of interferon genes, T-cell response and interferon-γ, which enables growth of high-TMB tumors. We have designated this as hepatic autophagy immune tolerance. Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load and autophagy inhibition is an effective means to promote an antitumor T-cell response in high-TMB tumors.

Author Correction: Autophagy maintains tumour growth through circulating arginine.

In this Letter, 'released' should have been 'regulated' in the sentence starting: 'Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...' This has been corrected online.

Autophagy maintains tumour growth through circulating arginine.

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.

Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization.

Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by encoding and delivering immunostimulatory molecules. This combination makes them an effective platform for the development of immunotherapeutic strategies beyond their primary lytic function. Engineering the viruses to also express tumor-associated antigens (TAAs) allows them to simultaneously serve as therapeutic vaccines, targeting and amplifying an immune response to TAAs. Our group and others have shown that vaccinating intratumorally with a poxvirus that encodes TAAs, in addition to immune stimulatory molecules, can modulate the tumor microenvironment, overcome immune inhibitory pathways, and drive both local and systemic tumor specific immune responses.

The post-2015 development agenda: keeping our focus on the worst off.

Non-communicable diseases now account for the majority of the global burden of disease and an international campaign has emerged to raise their priority on the post-2015 development agenda. We argue, to the contrary, that there remain strong reasons to prioritize maternal and child health. Policy-makers ought to assign highest priority to the health conditions that afflict the worst off. In virtue of how little healthy life they have had, children who die young are among the globally worst off. Moreover, many interventions to deal with the conditions that cause mortality in the young are low-cost and provide great benefits to their recipients. Consistent with the original Millennium Development Goals, the international community should continue to prioritize reductions in communicable diseases, neonatal conditions, and maternal health despite the shifts in the global burden of disease.

Prostaglandin H synthase Type 2 is differentially expressed in endometrium based on pregnancy status in pony mares and responds to oxytocin and conceptus secretions in explant culture.

The equine embryo must signal its presence to the uterus for pregnancy to continue to term. Mobility of the conceptus throughout the uterus is crucial for its survival, and this action presumably permits the conceptus to transmit its antiluteolytic signal to the endometrium. Studies were completed to establish whether this unidentified antiluteolytic signal targets prostaglandin G/H synthase 2 (PGHS2), a rate limiting enzyme in converting arachidonic acid to prostaglandins (PGs). In the first study, quantitative RT-PCR was used to determine the relative abundance of PGHS2 mRNA in endometrium derived from estrous cyclic and pregnant mares on day 14 post-ovulation. PGHS2 mRNA abundance was substantially greater in endometrium from estrous cyclic mares. Additional studies were completed to better understand PGHS2 in equine endometrium. An estrogen and progesterone treatment regimen in ovariectomized mares was developed as a test model for detecting endometrial PGHS2 mRNA. Also, exposing endometrial explants to conceptus secretions (conditioned culture medium) decreased PGHS2 mRNA abundance whereas exposing explants to oxytocin increased PGHS2 mRNA abundance. Exposure to conceptus secretions also decreased PGF2alpha concentrations in explant-conditioned medium whereas oxytocin supplementation increased PGF2alpha concentrations in medium. These data support the hypothesis that PGHS2 is a target for the antiluteolytic signal produced by equine conceptuses during early pregnancy. Also, the endometrial explant culture system used for these studies can serve as a model for identifying and characterizing the maternal recognition of pregnancy factor in equids.

Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis.

BACKGROUND: Sublingual swallow immunotherapy has been increasingly recognized as a safe and efficacious alternative to parenteral specific immunotherapy. OBJECTIVE: To determine the safety and efficacy of sublingual swallow immunotherapy ragweed allergen extract for rhinoconjunctivitis treatment starting just before and continuing through the ragweed pollen season. METHODS: This randomized, double-blind, placebo-controlled study was performed in children and adults with a documented history of allergic rhinoconjunctivitis during ragweed season at 9 Canadian allergy centers. Active treatment was standardized extract of ragweed allergen administered as sublingual swallow drops at increasing doses starting shortly before the pollen season and maintenance doses continued daily during the season. Primary efficacy variables were symptom and medication scores, and secondary variables included global evaluation of efficacy and immunologic measurements. RESULTS: Eighty-three patients were included in the safety analysis; 76 patients were included in the intent-to-treat analysis. Nine placebo recipients and 1 treatment recipient withdrew for lack of efficacy (P = .004). Nine patients in the treatment group withdrew because of adverse events, none serious (P = .003). Investigator evaluation of efficacy showed that significantly more patients improved and fewer deteriorated in the treatment group vs the placebo group (P = .047). Ragweed IgE and IgG4 levels increased significantly in treatment recipients vs placebo users (P < .001). Sneezing and nasal pruritus approached significant improvement in the treatment group vs the placebo group (P = .09 and .06, respectively). Quebec City experienced low pollen counts. Excluding Quebec City, significant improvement was seen for these 2 symptoms (P = .04). CONCLUSION: Sublingual swallow immunotherapy seems to be safe and efficacious for ragweed rhinoconjunctivitis even when started immediately before the ragweed pollen season.