Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma
In conclusion, the combination of HSP70 with phloretin could be a novel treatment for efficient immunotherapy of intractable cancers such as skin melanoma. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 8, 2015 Category: Cancer & Oncology Source Type: research

Low intratumoral regulatory T cells and high peritumoral CD8 + T cells relate to long-term survival in patients with pancreatic ductal adenocarcinoma after pancreatectomy
Abstract The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Recent studies have focused on the role of lymphocytes in the PDAC microenvironment. Using immunohistochemistry, our study explored the clinical significance of intratumoral or peritumoral CD4+Foxp3+ regulatory T cells (Tregs) and CD8+ T cells in the tumor microenvironment and analyzed their relation to the prognosis of PDAC in a consecutive series of 92 patients after resection. CD8+ T cells were more frequently seen within peritumoral sites, while CD4+Foxp3+ Tregs were more frequent within intratumoral areas. Neither e...
Source: Cancer Immunology, Immunotherapy - December 8, 2015 Category: Cancer & Oncology Source Type: research

Improving cancer immunotherapy with DNA methyltransferase inhibitors
Abstract Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of actio...
Source: Cancer Immunology, Immunotherapy - December 8, 2015 Category: Cancer & Oncology Source Type: research

Cholesterol metabolites and tumor microenvironment: the road towards clinical translation
Abstract Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key meta...
Source: Cancer Immunology, Immunotherapy - December 8, 2015 Category: Cancer & Oncology Source Type: research

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 suppresses tumor growth in breast cancer-bearing mice by negatively regulating myeloid-derived suppressor cell functions
Abstract Myeloid-derived suppressor cells (MDSCs) are one of the most important cell types that contribute to negative regulation of immune responses in the tumor microenvironment. Recently, aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1), a novel pleiotropic cytokine, was identified as an antitumor protein that inhibits angiogenesis and induces antitumor responses. However, the effect of AIMP1 on MDSCs in the tumor environment remains unclear. In the present study, we demonstrated that AIMP1 significantly inhibited tumor growth in 4T1 breast cancer-bearing mice and reduced MDSCs population...
Source: Cancer Immunology, Immunotherapy - November 27, 2015 Category: Cancer & Oncology Source Type: research

Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance
Abstract Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss...
Source: Cancer Immunology, Immunotherapy - November 26, 2015 Category: Cancer & Oncology Source Type: research

Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors
Abstract Radiotherapy (RT) utilizes the DNA-damaging properties of ionizing radiation to control tumor growth and ultimately kill tumor cells. By modifying the tumor cell phenotype and the tumor microenvironment, it may also modulate the immune system. However, out-of-field reactions of RT mostly assume further immune activation. Here, the sequence of the applications of RT and immunotherapy is crucial, just as the dose and fractionation may be. Lower single doses may impact on tumor vascularization and immune cell infiltration in particular, while higher doses may impact on intratumoral induction and production o...
Source: Cancer Immunology, Immunotherapy - November 21, 2015 Category: Cancer & Oncology Source Type: research

Biomarkers related to immunosenescence: relationships with therapy and survival in lung cancer patients
Conclusions Distribution of lymphocyte subsets was influenced by cancer and chemotherapy in NSCLC patients. CD19 + B cells decrease by cancer disease and not by chemotherapy, and CD28− subpopulations increase by chemotherapy and not by cancer. The proportion of CD8 + CD28− T cells, CD4+ T cells and CD4/CD8 ratio can be used as predictive biomarkers of CIMAvax-EGF efficacy in NSCLC patients and thereby could, be a useful tool for a personalized treatment. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 20, 2015 Category: Cancer & Oncology Source Type: research

A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites
Conclusion The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4+ T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 18, 2015 Category: Cancer & Oncology Source Type: research

Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis
In this study, we aimed to determine the relative importance of IL-17A and the master regulator of the Th17 pathway, the transcription factor RORγt, in the sporadic intestinal neoplasia of APCMIN/+ mice and in human colorectal cancer. We show that levels of IL-17A are increased in human colon cancer as compared to adjacent uninvolved colon. Similarly, naïve helper T cells from colorectal cancer patients are more inducible into the Th17 pathway. Furthermore, IL-17A, IL-21, IL-22, and IL-23 are all demonstrated to be directly mitogenic to human colorectal cancer cell lines. Nevertheless, deficiency of IL-17A but n...
Source: Cancer Immunology, Immunotherapy - November 11, 2015 Category: Cancer & Oncology Source Type: research

NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy
Abstract Natural killer (NK) cells are increasingly considered as immunotherapeutic agents in particular in the fight against cancers. NK cell therapies are potentially broadly applicable and, different from their T cell counterparts, do not cause graft-versus-host disease. Efficacy and clinical in vitro or in vivo expansion of primary NK cells will however always remain variable due to individual differences of donors or patients. Long-term storage of clinical NK cell lots to allow repeated clinical applications remains an additional challenge. In contrast, the established and well-characterized cell line NK-92 c...
Source: Cancer Immunology, Immunotherapy - November 11, 2015 Category: Cancer & Oncology Source Type: research

Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells
Abstract Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastase...
Source: Cancer Immunology, Immunotherapy - November 5, 2015 Category: Cancer & Oncology Source Type: research

Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone
Abstract Chimeric antigen receptor (CAR)-modified T cells emerged as effective tools in the immunotherapy of cancer but can produce severe on-target off-tissue toxicities. This risk can conceivably be overcome, at least partially, by transient transfection. The design of CARs, however, has so far not been optimized for use in non-permanent T cell modification. Here we compared the performance of T cells modified with three different first- and second-generation CARs, each specific for MCSP (HMW-MAA) which is commonly expressed by melanoma cells. Upon RNA transfer, the expression of all receptors was limited i...
Source: Cancer Immunology, Immunotherapy - October 29, 2015 Category: Cancer & Oncology Source Type: research

Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination
Abstract We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4+CD25+CD127low/&m...
Source: Cancer Immunology, Immunotherapy - October 26, 2015 Category: Cancer & Oncology Source Type: research

Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator
Abstract The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR−CD33+CD11b+ MDSCs was observed in ENKL patients than in healthy controls (P 60 %) and CD15+ granulocytic (PMN-MDSCs,
Source: Cancer Immunology, Immunotherapy - October 23, 2015 Category: Cancer & Oncology Source Type: research

Increased tumor infiltration by mucosal-associated invariant T cells correlates with poor survival in colorectal cancer patients
This study suggests that including MAIT-cell-specific markers or transcripts in the analysis of tumor-infiltrating lymphocytes could be a benefit to the diagnosis and follow-up of CRC patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 23, 2015 Category: Cancer & Oncology Source Type: research

Novel angiogenin mutants with increased cytotoxicity enhance the depletion of pro-inflammatory macrophages and leukemia cells ex vivo
Abstract Immunotoxins are fusion proteins that combine a targeting component such as an antibody fragment or ligand with a cytotoxic effector component that induces apoptosis in specific cell populations displaying the corresponding antigen or receptor. Human cytolytic fusion proteins (hCFPs) are less immunogenic than conventional immunotoxins because they contain human pro-apoptotic enzymes as effectors. However, one drawback of hCFPs is that target cells can protect themselves by expressing endogenous inhibitor proteins. Inhibitor-resistant enzyme mutants that maintain their cytotoxic activity are therefore prom...
Source: Cancer Immunology, Immunotherapy - October 15, 2015 Category: Cancer & Oncology Source Type: research

Analogue peptides for the immunotherapy of human acute myeloid leukemia
Abstract The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. ...
Source: Cancer Immunology, Immunotherapy - October 5, 2015 Category: Cancer & Oncology Source Type: research

Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients
Abstract Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (...
Source: Cancer Immunology, Immunotherapy - October 1, 2015 Category: Cancer & Oncology Source Type: research

Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer
Abstract The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ in...
Source: Cancer Immunology, Immunotherapy - September 30, 2015 Category: Cancer & Oncology Source Type: research

Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy
This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 30, 2015 Category: Cancer & Oncology Source Type: research

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials’ experience
Conclusion These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age 64 years. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 21, 2015 Category: Cancer & Oncology Source Type: research

Modification of cytokine-induced killer cells with chimeric antigen receptors (CARs) enhances antitumor immunity to epidermal growth factor receptor (EGFR)-positive malignancies
Abstract Epidermal growth factor receptor (EGFR, ErbB1, Her-1) is a cell surface molecule overexpressing in a variety of human malignancies and, thus, is an excellent target for immunotherapy. Immunotherapy targeting EGFR-overexpressing malignancies using genetically modified immune effector cells is a novel and promising approach. In the present study, we have developed an adoptive cellular immunotherapy strategy based on the chimeric antigen receptor (CAR)-modified cytokine-induced killer (CAR-CIK) cells specific for the tumor cells expressing EGFR. To generate CAR-CIK cells, a lentiviral vector coding the EGFR-...
Source: Cancer Immunology, Immunotherapy - September 19, 2015 Category: Cancer & Oncology Source Type: research

Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies
Abstract Different approaches have been explored to raise effective antitumor responses against glioblastoma (GBM), the deadliest of primary brain tumors. In many clinical studies, cancer vaccines have been based on dendritic cells (DCs) loaded with peptides, representing one or more specific tumor antigens or whole lysates as a source of multiple antigens. Randomized clinical trials using DCs are ongoing, and results of efficacy are not yet available. Such strategies are feasible and safe; however, immune-suppressive microenvironment, absence of appropriate specific epitopes to target, and cancer immunoediting ca...
Source: Cancer Immunology, Immunotherapy - September 16, 2015 Category: Cancer & Oncology Source Type: research

RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML
Abstract Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples b...
Source: Cancer Immunology, Immunotherapy - September 16, 2015 Category: Cancer & Oncology Source Type: research

Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer
In this study, we used immunofluorescence-based microscopy to enumerate Tregs, total CD4 T cells, and CD8+ cytotoxic T cells in fresh frozen tumors from over 400 patients with ovarian cancer (>80 % high-grade serous). We sought to determine whether Tregs were associated with survival and genetic variation in 79 genes known to influence Treg induction, trafficking, or function. We used Cox regression, accounting for known prognostic factors, to estimate hazard ratios (HRs) associated with T cell counts and ratios. We found that the ratios of CD8 T cells and total CD4 T cells to Tregs were associated with improved ov...
Source: Cancer Immunology, Immunotherapy - August 22, 2015 Category: Cancer & Oncology Source Type: research

Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias
Abstract It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell f...
Source: Cancer Immunology, Immunotherapy - August 20, 2015 Category: Cancer & Oncology Source Type: research

Dysfunction of PSA-specific CD8 + T cells in prostate cancer patients correlates with CD38 and Tim-3 expression
Abstract The efficacy of immunotherapy in cancer patients is influenced by differences in their immune status. An evaluation of immunocompetence before therapy may help to predict therapeutic success and guide the selection of appropriate regimens. We assessed the preexisting cellular immunity against prostate-specific antigen (PSA) in untreated prostate cancer patients and healthy controls through measurement of the phenotype and function of CD8+ T cells. Our data show that the majority of healthy men possess functional PSA-specific CD8+ T cells in contrast to cancer patients, where
Source: Cancer Immunology, Immunotherapy - August 20, 2015 Category: Cancer & Oncology Source Type: research

Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance
Abstract A key feature of human natural killer (NK) cells, which enables efficient recognition of infected and malignant target cells, is the expression of HLA class I-specific receptors of the KIR and NKG2 gene families. Cell-to-cell variability in receptor expression leads to the formation of complex NK cell repertoires. As outlined here, NK cells go through major changes from newborns to adults characterized by downregulation of the inhibitory NKG2A receptor and concomitant upregulation of KIR family members. This process is completed in young adults, and in the majority of individuals, KIR/NKG2A repertoires re...
Source: Cancer Immunology, Immunotherapy - August 19, 2015 Category: Cancer & Oncology Source Type: research

Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients
Abstract CD4+FoxP3+ regulatory T cells (Tregs) represent a major cellular mediator of cancer immune evasion. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. We therefore investigated the phenotype and function of TNFR2+ Tregs present in the peripheral blood (PB) of 43 lung cancer patients. Further, the association of TNFR2 expression on Tregs with clinicopathological factors was analyzed. The results showed that in the PB of lung cancer patients, Tregs expressed markedly higher levels of TNFR2 than c...
Source: Cancer Immunology, Immunotherapy - August 18, 2015 Category: Cancer & Oncology Source Type: research

Protamine-stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets
Abstract Dendritic cells (DCs) are key in connecting innate and adaptive immunity. Their potential in inducing specific immune responses has made them interesting targets for immunotherapeutic approaches. Our research group was the first to exploit the naturally occurring myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in therapeutic vaccination trials against melanoma. To develop primary DC subsets as an optimal vaccine, the identification of a clinically applicable adjuvant activating both subsets is required. Although the expression of pathogen recognition receptors differs distinctly between the DC subsets, bot...
Source: Cancer Immunology, Immunotherapy - August 15, 2015 Category: Cancer & Oncology Source Type: research

Targeting tumor vasculature: expanding the potential of DNA cancer vaccines
Abstract Targeting the tumor vasculature with anti-angiogenesis modalities is a bona fide validated approach that has complemented cancer treatment paradigms. Tumor vasculature antigens (TVA) can be immunologically targeted and offers multiple theoretical advantages that may enhance existing strategies against cancer. We focused on tumor endothelial marker 1 (TEM1/CD248) as a model TVA since it is broadly expressed on many different cancers. Our DNA-based vaccine approach demonstrated that CD248 can be effectively targeted immunologically; anti-tumor responses were generated in several mouse models; and CD8+/CD4+ ...
Source: Cancer Immunology, Immunotherapy - August 12, 2015 Category: Cancer & Oncology Source Type: research

Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015
Abstract Immunotherapy targeting “immune checkpoints” first made the headlines at the ASCO (American Society of Clinical Oncology) Annual Meeting in 2013, took centre stage at 2014 and consolidated its position as a potentially curative first-line therapy as reflected by the presentations at ASCO 2015. For the first time, previously refractory cancers are proving amenable to treatment, but still only a fraction, usually a minority, of patients respond. The hunt for factors predicting responses and for biomarkers to monitor treatment was a major theme of this year’s meeting, as briefly discussed i...
Source: Cancer Immunology, Immunotherapy - August 12, 2015 Category: Cancer & Oncology Source Type: research

Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment
Abstract The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in ...
Source: Cancer Immunology, Immunotherapy - August 7, 2015 Category: Cancer & Oncology Source Type: research

Gene expression patterns in CD4+ peripheral blood cells in healthy subjects and stage IV melanoma patients
Abstract Melanoma patients exhibit changes in immune responsiveness in the local tumor environment, draining lymph nodes, and peripheral blood. Immune-targeting therapies are revolutionizing melanoma patient care increasingly, and studies show that patients derive clinical benefit from these newer agents. Nonetheless, predicting which patients will benefit from these costly therapies remains a challenge. In an effort to capture individual differences in immune responsiveness, we are analyzing patterns of gene expression in human peripheral blood cells using RNAseq. Focusing on CD4+ peripheral blood cells, we d...
Source: Cancer Immunology, Immunotherapy - August 6, 2015 Category: Cancer & Oncology Source Type: research

The impact of leukapheresis on immune-cell number and function in patients with advanced cancer
Conclusions These data provide evidence that leukapheresis has no detectable effects on a cancer patient’s immune system in terms of number or function. These results contribute to a growing body of evidence refuting the hypothesis that a patient’s immune competence is meaningfully affected by the procedure. Limitations include a restriction to 2-L leukapheresis procedure and small sample size. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - August 5, 2015 Category: Cancer & Oncology Source Type: research

Differential capacity of human interleukin-4 and interferon-α monocyte-derived dendritic cells for cross-presentation of free versus cell-associated antigen
In conclusion, our data indicate the use of IFNα MoDC over IL-4 MoDC in the context of DC vaccination with SLP, whereas IL-4 MoDC are preferred for vaccination with bleb-derived antigens. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - July 28, 2015 Category: Cancer & Oncology Source Type: research

Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma
Abstract Cancer-associated fibroblasts (CAFs) have been shown to play an important role in angiogenesis, invasion, and metastasis. In the present study, we determined whether CAFs within the tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) contributed to promoting immunosuppression and evasion from immune surveillance. Six pairs of CAFs and normal fibroblasts (NFs) were established from the resected tumor tissues of patients with HNSCC. The effects of CAFs and NFs on the functions of T cells were comparatively analyzed. CAFs expressed the co-regulatory molecules, B7H1 and B7DC, whe...
Source: Cancer Immunology, Immunotherapy - July 23, 2015 Category: Cancer & Oncology Source Type: research

Cytokine-enhanced maturation and migration to the lymph nodes of a human dying melanoma cell-loaded dendritic cell vaccine
Abstract Dendritic cells (DCs) are professional APCs used for the development of cancer vaccines because of their ability to activate adaptive immune responses. Previously, we designed the DC/Apo-Nec vaccine using human DCs loaded with dying melanoma cells that primed Ag-specific cytotoxic T cells. Here, we evaluate the effect of a standard pro-inflammatory cytokine cocktail (CC) and adjuvants on DC/Apo-Nec maturation and migration. CC addition to the vaccine coculture allowed efficient Ag uptake while attaining strong vaccine maturation with an immunostimulatory profile. The use of CC not only increased CCR7 expr...
Source: Cancer Immunology, Immunotherapy - July 22, 2015 Category: Cancer & Oncology Source Type: research

Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway
Abstract The programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been shown to be involved in tumor-induced and sepsis-induced immunosuppression. However, whether this pathway is involved in the surgery-induced dysfunction of T lymphocytes is not known. Here, we analyzed expression of PD-1 and PD-L1 on human peripheral mononuclear cells during the perioperative period. We found that surgery increased PD-1/PD-L1 expression on immune cells, which was correlated with the severity of surgical trauma. The count of T lymphocytes and natural killer cells reduced after surgery, probably due to the...
Source: Cancer Immunology, Immunotherapy - July 17, 2015 Category: Cancer & Oncology Source Type: research

T cell responses in early-stage melanoma patients occur frequently and are not associated with humoral response
Abstract Endogenous tumor-specific T cells are detectable in patients with different tumor types including malignant melanoma (MM). They can control tumor growth, have impact on patient survival and correlate with improved clinical response to immune checkpoint therapy. Thus, they may represent a potent biomarker for respective treatment decisions. So far, major target antigens of endogenous MM-reactive T cells have not been determined systematically. Instead, autoantibodies are discussed as surrogate parameter for MM-specific T cells. Throughout a period of more than 60 days after tumor resection, we therefo...
Source: Cancer Immunology, Immunotherapy - July 10, 2015 Category: Cancer & Oncology Source Type: research

Immunotherapy of HPV-associated cancer: DNA/plant-derived vaccines and new orthotopic mouse models
Abstract Under the optimistic assumption of high-prophylactic HPV vaccine coverage, a significant reduction of cancer incidence can only be expected after decades. Thus, immune therapeutic strategies are needed for persistently infected individuals who do not benefit from the prophylactic vaccines. However, the therapeutic strategies inducing immunity to the E6 and/or E7 oncoprotein of HPV16 are more effective for curing HPV-expressing tumours in animal models than for treating human cancers. New strategies/technologies have been developed to improve these therapeutic vaccines. Our studies focussed on preparing th...
Source: Cancer Immunology, Immunotherapy - July 3, 2015 Category: Cancer & Oncology Source Type: research

Hepatic myeloid-derived suppressor cells in cancer
Abstract Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients. The liver, continuously exposed to food and microbial antigens from the intestine, avoids autoimmune damage through the use of specialized mechanisms of immune tolerance. In the context of...
Source: Cancer Immunology, Immunotherapy - July 2, 2015 Category: Cancer & Oncology Source Type: research

Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry
In conclusion, we propose an essential marker set comprising antibodies to CD3, CD4, CD25, CD127, Foxp3, Ki67, and CD45RA and a corresponding robust gating strategy for the context-dependent analysis of Tregs by flow cytometry. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 28, 2015 Category: Cancer & Oncology Source Type: research

Expansion of myeloid-derived suppressor cells in chronic obstructive pulmonary disease and lung cancer: potential link between inflammation and cancer
Conclusions These results suggest that tumor immunosurveillance might be impaired in COPD and may contribute to the increased risk of LC reported in these patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 28, 2015 Category: Cancer & Oncology Source Type: research

A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma
Abstract Antigen-specific immunotherapy was studied in a multi-institutional phase 1/2 study by combining decitabine (DAC) followed by an autologous dendritic cell (DC)/MAGE-A1, MAGE-A3 and NY-ESO-1 peptide vaccine in children with relapsed/refractory solid tumors. Patients aged 2.5–15 years with relapsed neuroblastoma, Ewing’s sarcoma, osteosarcoma and rhabdomyosarcoma were eligible to receive DAC followed by DC pulsed with overlapping peptides derived from full-length MAGE-A1, MAGE-A3 and NY-ESO-1. The primary endpoints were to assess the feasibility and tolerability of this regimen. Each of...
Source: Cancer Immunology, Immunotherapy - June 24, 2015 Category: Cancer & Oncology Source Type: research

Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma
Abstract Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered t...
Source: Cancer Immunology, Immunotherapy - June 24, 2015 Category: Cancer & Oncology Source Type: research

Developments in cancer vaccines for hepatocellular carcinoma
Abstract Hepatocellular carcinoma (HCC) accounts for about 6 % of all new cancers diagnosed worldwide and represents one of the leading causes of cancer-related death globally in men and women, respectively. The overall prognosis for HCC patients is poor, especially in the majority of patients with more advanced stage of disease. Indeed, in such cases immunotherapeutic strategies may represent a novel and effective tool. A few immunotherapy trials conducted for HCC have provided divergent results, urging the scientific community to explore additional paths to improve efficacy of immunotherapeutic approach...
Source: Cancer Immunology, Immunotherapy - June 21, 2015 Category: Cancer & Oncology Source Type: research

TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice
Abstract Systemic administration of small molecule toll-like receptor (TLR)-7 agonists leads to potent activation of innate immunity and to the generation of anti-tumor immune responses. However, activation of TLRs with small molecule agonists may lead to the induction of TLR tolerance, defined as a state of hyporesponsiveness to subsequent agonism, which may limit immune activation, the generation of anti-tumor responses and clinical response. Our data reveal that dose scheduling impacts on the efficacy of systemic therapy with the selective TLR7 agonist, 6-amino-2-(butylamino)-9-((6-(2-(dimethylamino)ethoxy)pyri...
Source: Cancer Immunology, Immunotherapy - June 20, 2015 Category: Cancer & Oncology Source Type: research

Targeting of MYCN by means of DNA vaccination is effective against neuroblastoma in mice
Abstract The MYCN oncogene is a strong genetic marker associated with poor prognosis in neuroblastoma (NB). Therefore, MYCN gene amplification and subsequent overexpression provide a possible target for new treatment approaches in NB. We first identified an inverse correlation of MYCN expression with CD45 mRNA in 101 NB tumor samples. KEGG mapping further revealed that MYCN expression was associated with immune-suppressive pathways characterized by a down-regulation of T cell activation and up-regulation of T cell inhibitory gene transcripts. We then aimed to investigate whether DNA vaccination against MYCN is eff...
Source: Cancer Immunology, Immunotherapy - June 16, 2015 Category: Cancer & Oncology Source Type: research