Intratumoral CD8⁺ T cells with stem cell-like properties: Implications for cancer immunotherapy.

Intratumoral PD-1 <sup>+</sup> TCF1 <sup>+</sup> CD8 <sup>+</sup> T cells with stem cell-like properties mediate cellular expansion and tumor control in response to immunotherapy

Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma.

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients' prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma

New Lithium Measurements in Metal-Poor Stars

We provide *lambda*6708 Li 1 measurements in 37 metal-poor stars, most of which are poorly-studied or have no previous measurements, from high-resolution and high-S/N spectroscopy obtained with the McDonald Observatory 2.1m and 2.7m telescopes. The typical line strength and abundance uncertainties, confirmed by the thinness of the Spite plateau manifested by our data and by comparison with previous measurements, are <=4 mAng and <=0.07-0.10 dex respectively. Two rare moderately metal-poor solar-Teff dwarfs, HIP 36491 and 40613, with significantly depleted but still detectable Li are identified; future light element determinations in the more heavily depeleted HIP 40613 may provide constraints on the Li depletion mechanism acting in this star. We note two moderately metal-poor and slightly evolved stars, HIP 105888 and G265-39, that appear to be analogs of the low-Li moderately metal-poor subgiant HD 201889. Preliminary abundance analysis of G 265-39 finds no abnormalities that suggest the low Li content is associated with AGB mass-transfer or deep mixing and p-capture. We also detect line doubling in HIP 4754, heretofore classified as SB1.Comment: Accepted for publication in PASP, volume 912 (Feb 2012) 15 pages, 3 figures, 2 table

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma.

Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8 &lt;sup&gt;+&lt;/sup&gt; T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance

Intracellular coexpression of CXC- and CC– chemokine receptors and their ligands in human melanoma cell lines and dynamic variations after xenotransplantation

BackgroundChemokines have been implicated in tumor progression and metastasis. In melanoma, chemokine receptors have been implicated in organ selective metastasis by regulating processes such as chemoattraction, adhesion and survival.MethodsIn this study we have analyzed, using flow cytometry, the systems formed by the chemokine receptors CXCR3, CXCR4, CXCR7, CCR7 and CCR10 and their ligands in thirteen human melanoma cell lines (five established from primary tumors and eight established from metastasis from different tissues). WM-115 and WM-266.4 melanoma cell lines (obtained from a primary and a metastatic melanoma respectively) were xenografted in nude mice and the tumors and cell lines derived from them were also analyzed.ResultsOur results show that the melanoma cell lines do not express or express in a low degree the chemokine receptors on their cell surface. However, melanoma cell lines show intracellular expression of all the aforementioned receptors and most of their respective ligands. When analyzing the xenografts and the cell lines obtained from them we found variations in the intracellular expression of chemokines and chemokine receptors that differed between the primary and metastatic cell lines. However, as well as in the original cell lines, minute or no expression of the chemokine receptors was observed at the cell surface.ConclusionsCoexpression of chemokine receptors and their ligands was found in human melanoma cell lines. However, this expression is intracellular and receptors are not found at the cell membrane nor chemokines are secreted to the cell medium. The levels of expressed chemokine receptors and their ligands show dynamic variations after xenotransplantation that differ depending on the origin of the cell line (from primary tumor or from metastasis)

CD4+ T cells in cancer.

Cancer immunology and immunotherapy are driving forces of research and development in oncology, mostly focusing on CD8 &lt;sup&gt;+&lt;/sup&gt; T cells and the tumor microenvironment. Recent progress highlights the importance of CD4 &lt;sup&gt;+&lt;/sup&gt; T cells, corresponding to the long-known fact that CD4 &lt;sup&gt;+&lt;/sup&gt; T cells are central players and coordinators of innate and antigen-specific immune responses. Moreover, they have now been recognized as anti-tumor effector cells in their own right. Here we review the current status of CD4 &lt;sup&gt;+&lt;/sup&gt; T cells in cancer, which hold great promise for improving knowledge and therapies in cancer

Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts.

Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection

Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.

Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD &lt;sup&gt;+&lt;/sup&gt; ) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD &lt;sup&gt;+&lt;/sup&gt; biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet

Genome scan for childhood and adolescent obesity in German families

Objective. Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. Methods. The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 ± 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. Results. The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. Conclusion. We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity