An increased abundance of tumor-infiltrating regulatory t cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma

CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the tumor microenvironment. Thus, the potential role of intratumoral Tregs in PDA patients remains to be elucidated. In this study, we found that the percentages of Tregs, CD4+ T cells and CD8+ T cells were all increased significantly in tumor tissue compared to control pancreatic tissue, as assessed via FCM, whereas the percentages of these cell types in PBMCs did not differ between PDA patients and healthy volunteers. The percentages of CD8 + T cells in tumors were significantly lower than in PDA patient PBMCs. In addition, the relative numbers of CD4+CD25+Foxp3+ Tregs and CD8+ T cells were negatively correlated in the tissue of PDA patients, and the abundance of Tregs was significantly correlated with tumor differentiation. Additionally, Foxp3+ T cells were observed more frequently in juxtatumoral stroma (immediately adjacent to the tumor epithelial cells). Patients showing an increased prevalence of Foxp3+ T cells had a poorer prognosis, which was an independent factor for patient survival. These results suggest that Tregs may promote PDA progression by inhibiting the antitumor immunity of CD8+ T cells at local intratumoral sites. Moreover, a high proportion of Tregs in tumor tissues may reflect suppressed antitumor immunity. Copyright: © 2014 Tang et al

A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma

Background: The sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches. Immunotherapy is a promising option that deserves major investigation. In this open label, single arm clinical trial, we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide (GV1001) vaccination in patients with advanced HCC. Methods: 40 patients with advanced HCC were treated with 300 mg/m(2) cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1, 3, 5, 8, 15, 22, 36 followed by 4-weekly injections. Primary endpoint of this phase II trial was tumor response; secondary endpoints evaluated were TTP, TTSP, PFS, OS, safety and immune responses. Results: None of the patients had a complete or partial response to treatment, 17 patients (45.9%) demonstrated a stable disease six months after initiation of treatment. The median TTP was 57.0 days; the median TTSP was estimated to be 358.0 days. Cyclophosphamide, GV1001 and GM-CSF treatment were well tolerated and most adverse events, which were of grade 1 or 2, were generally related to the injection procedure and injection site reactions. GV1001 treatment resulted in a decrease in CD4(+)CD25(+)Foxp3(+) regulatory T cells; however, no GV1001 specific immune responses were detected after vaccination. Conclusions: Low dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression. Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC. Trial registration: NCT00444782Pharmexa A/S Bioscience

CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?

The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy

Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer

BioMed CentralIntroduction Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. Methods The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. Results In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.This study was supported by funding from the Canadian Institutes of Health Research (CIHR, grant MOP-64349) and the BC Cancer Foundation. The Manitoba Breast Tumor Bank, a member of the Canadian Tumor Repository Network, is supported by CIHR grant PRG80155. NRW is supported by a US DOD Breast Cancer Research Program predoctoral traineeship award (W81XWH-08-1-0781).FacultyReviewe

Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion

Antibiotic resistance determinants in the interplay between food and gut microbiota

A complex and heterogeneous microflora performs sugar and lactic acid fermentations in food products. Depending on the fermentable food matrix (dairy, meat, vegetable etc.) as well as on the species composition of the microbiota, specific combinations of molecules are produced that confer unique flavor, texture, and taste to each product. Bacterial populations within such “fermented food microbiota” are often of environmental origin, they persist alive in foods ready for consumption, eventually reaching the gastro-intestinal tract where they can interact with the resident gut microbiota of the host. Although this interaction is mostly of transient nature, it can greatly contribute to human health, as several species within the food microbiota also display probiotic properties. Such an interplay between food and gut microbiota underlines the importance of the microbiological quality of fermented foods, as the crowded environment of the gut is also an ideal site for genetic exchanges among bacteria. Selection and spreading of antibiotic resistance genes in foodborne bacteria has gained increasing interest in the past decade, especially in light of the potential transferability of antibiotic resistance determinants to opportunistic pathogens, natural inhabitants of the human gut but capable of acquiring virulence in immunocompromised individuals. This review aims at describing major findings and future prospects in the field, especially after the use of antibiotics as growth promoters was totally banned in Europe, with special emphasis on the application of genomic technologies to improve quality and safety of fermented foods

T Cells Specifically Targeted to Amyloid Plaques Enhance Plaque Clearance in a Mouse Model of Alzheimer's Disease

Patients with Alzheimer's disease (AD) exhibit substantial accumulation of amyloid-β (Aβ) plaques in the brain. Here, we examine whether Aβ vaccination can facilitate the migration of T lymphocytes to specifically target Aβ plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Aβ, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Aβ plaques in the brain. Although both Aβ-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-γ, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Aβ T cells accumulated primarily at Aβ plaques in the brain but not the spinal cord and induced almost complete clearance of Aβ. Furthermore, while a single vaccination with Aβ resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-β1 (SIRPβ1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-α and IL-6. We thus suggest that Aβ deposits in the hippocampus area prioritize the targeting of Aβ-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Aβ-reactive T cells at sites of Aβ plaques resulted in IFN-γ-induced chemotaxis of leukocytes and therapeutic clearance of Aβ