Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice.

Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)+ in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A Mediterranean-like fat blend protects against the development of severe colitis in the mucin-2 deficient murine model.

There is a growing appreciation that the interaction between diet, the gut microbiota and the immune system contribute to the development and progression of inflammatory bowel disease (IBD). A mounting body of scientific evidence suggests that high-fat diets exacerbate IBD; however, there is a lack of information on how specific types of fat impact colitis. The Mediterranean diet (MD) is considered a health-promoting diet containing approximately 40% total fat. It is not known if the blend of fats found in the MD contributes to its beneficial protective effects.Mice deficient in the mucin 2 gene (Muc 2-/-) were weaned to 40% fat, isocaloric, isonitrogenous diets. We compared the MD fat blend (high monounsaturated, 2:1 n-6:n-3 polyunsaturated and moderate saturated fat) to diets composed of corn oil (CO, n-6 polyunsaturated-rich), olive oil (monounsaturated-rich) or milk fat (MF, saturated-rich) on spontaneous colitis development in Muc2-/- mice. The MD resulted in lower clinical and histopathological scores and induced tolerogenic CD103+ CD11b+ dendritic, Th22 and IL-17+ IL-22+ cells necessary for intestinal barrier repair. The MD was associated with beneficial microbes and associated with higher cecal acetic acid levels negatively correlated with colitogenic microbes like Akkermansia muciniphila. In contrast, CO showed a higher prevalence of mucin-degraders including A. muciniphila and Enterobacteriaceae, which have been associated with colitis.A dietary blend of fats mimicking the MD, reduces disease activity, inflammation-related biomarkers and improves metabolic parameters in the Muc2-/- mouse model. Our findings suggest that the MD fat blend could be incorporated into a maintenance diet for colitis.

Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products.

The use of live biotherapeutic products (LBPs), including single strains of beneficial probiotic bacteria or consortiums, is gaining traction as a viable option to treat inflammatory-mediated diseases like inflammatory bowel disease (IBD). However, LBPs' persistence in the intestine is heterogeneous since many beneficial bacteria lack mechanisms to tolerate the inflammation and the oxidative stress associated with IBD. We rationalized that optimizing LBPs with enhanced colonization and persistence in the inflamed intestine would help beneficial bacteria increase their bioavailability and sustain their beneficial responses. Our lab developed two bioengineered LBPs (SBT001/BioPersist and SBT002/BioColoniz) modified to enhance colonization or persistence in the inflamed intestine. In this study, we examined colon-derived metabolites via ultra-high performance liquid chromatography-mass spectrometry in colitic mice treated with either BioPersist or BioColoniz as compared to their unmodified parent strains (Escherichia coli Nissle 1917 [EcN] and Lactobacillus reuteri, respectively) or to each other. BioPersist administration resulted in lowered concentrations of inflammatory prostaglandins, decreased stress hormones such as adrenaline and corticosterone, increased serotonin, and decreased bile acid in comparison to EcN. In comparison to BioColoniz, BioPersist increased serotonin and antioxidant production, limited bile acid accumulation, and enhanced tissue restoration via activated purine and pyrimidine metabolism. These data generated several novel hypotheses for the beneficial roles that LBPs may play during colitis.

Connecting the Dots Between Inflammatory Bowel Disease and Metabolic Syndrome: A Focus on Gut-Derived Metabolites.

The role of the microbiome in health and disease has gained considerable attention and shed light on the etiology of complex diseases like inflammatory bowel disease (IBD) and metabolic syndrome (MetS). Since the microorganisms inhabiting the gut can confer either protective or harmful signals, understanding the functional network between the gut microbes and the host provides a comprehensive picture of health and disease status. In IBD, disruption of the gut barrier enhances microbe infiltration into the submucosae, which enhances the probability that gut-derived metabolites are translocated from the gut to the liver and pancreas. Considering inflammation and the gut microbiome can trigger intestinal barrier dysfunction, risk factors of metabolic diseases such as insulin resistance may have common roots with IBD. In this review, we focus on the overlap between IBD and MetS, and we explore the role of common metabolites in each disease in an attempt to connect a common origin, the gut microbiome and derived metabolites that affect the gut, liver and pancreas.

Development of a functionalized UV-emitting nanocomposite for the treatment of cancer using indirect photodynamic therapy.

BACKGROUND: Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y2.99Pr0.01Al5O12-based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. RESULTS: A YP nanophosphor core was synthesized using the sol-gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptorFolr1, validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. CONCLUSION: Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface.