Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination with PD-1 mAb in a mouse model of prostate cancer
Abstract Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime–boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEA...
Source: Cancer Immunology, Immunotherapy - April 6, 2016 Category: Cancer & Oncology Source Type: research

Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands
In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation...
Source: Cancer Immunology, Immunotherapy - March 31, 2016 Category: Cancer & Oncology Source Type: research

Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice
Abstract Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, an...
Source: Cancer Immunology, Immunotherapy - March 31, 2016 Category: Cancer & Oncology Source Type: research

Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype
Abstract The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80+Nos2+ cel...
Source: Cancer Immunology, Immunotherapy - March 31, 2016 Category: Cancer & Oncology Source Type: research

2′–5′ Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons
In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 −/−) mice and transplantable syngeneic tumor cell models. We found that Oasl1 −/− mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8+ T cells (including tumor antigen-specific CD8+ T cells) and NK cells as well as CD8α+ DCs (the major antigen cross-presenting cells) were much more frequent (&...
Source: Cancer Immunology, Immunotherapy - March 31, 2016 Category: Cancer & Oncology Source Type: research

4-1BB agonism: adding the accelerator to cancer immunotherapy
Abstract The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB...
Source: Cancer Immunology, Immunotherapy - March 31, 2016 Category: Cancer & Oncology Source Type: research

Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model
Abstract Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-speci...
Source: Cancer Immunology, Immunotherapy - March 28, 2016 Category: Cancer & Oncology Source Type: research

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma
Abstract Background Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy. Materials and Methods Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarray...
Source: Cancer Immunology, Immunotherapy - March 28, 2016 Category: Cancer & Oncology Source Type: research

Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice
Abstract Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic chori...
Source: Cancer Immunology, Immunotherapy - March 24, 2016 Category: Cancer & Oncology Source Type: research

Non-small-cell lung cancer-induced immunosuppression by increased human regulatory T cells via Foxp3 promoter demethylation
Abstract Patients with non-small-cell lung cancer (NSCLC) have immune defects that are poorly understood. Forkhead box protein P3 (Foxp3) is crucial for immunosuppression by CD4+ regulatory T cells (Tregs). It is not well known how NSCLC induces Foxp3 expression and causes immunosuppression in tumor-bearing patients. Our study found a higher percentage of CD4+ Tregs in the peripheral blood of NSCLC compared with healthy donors. NSCLC patients showed demethylation of eight CpG sites within the Foxp3 promoter with methylation ratios negatively correlated with CD4+CD25+Foxp3+ T levels. Foxp3 expression in CD4+ Tregs ...
Source: Cancer Immunology, Immunotherapy - March 21, 2016 Category: Cancer & Oncology Source Type: research

Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors
In this study, we compared tumor-infiltrating CD3+, CD4+, CD8+ T-cells, and granzyme inhibitors (SERPINB1, SERPINB4, and SERPINB9) between HPV-positive and HPV-negative tumors and the relation with survival. Methods Protein expression of tumor-infiltrating lymphocytes (TILs) (CD3, CD4, and CD8) and granzyme inhibitors was analyzed in 262 OPSCCs by immunohistochemistry (IHC). Most patients (67 %) received primary radiotherapy with or without chemotherapy. Cox regression analysis was carried out to compare overall survival (OS) of patients with low and high TIL infiltration and ex...
Source: Cancer Immunology, Immunotherapy - March 18, 2016 Category: Cancer & Oncology Source Type: research

Tumor-derived factors modulating dendritic cell function
Abstract Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also imp...
Source: Cancer Immunology, Immunotherapy - March 16, 2016 Category: Cancer & Oncology Source Type: research

Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination
Abstract In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50 % at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected a...
Source: Cancer Immunology, Immunotherapy - March 15, 2016 Category: Cancer & Oncology Source Type: research

Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage?
Abstract CD137(4-1BB) costimulation and adoptive T cell therapy strongly synergize in terms of achieving maximal efficacy against experimental cancers. These costimulatory biological functions of CD137 have been exploited by means of introducing the CD137 signaling domain in clinically successful chimeric antigen receptors and to more efficiently expand T cells in culture. In addition, immunomagnetic sorting of CD137-positive T cells among tumor-infiltrating lymphocytes selects for the fittest antitumor T lymphocytes for subsequent cultures. In mouse models, co-infusion of both agonist antibodies and T cells attai...
Source: Cancer Immunology, Immunotherapy - March 12, 2016 Category: Cancer & Oncology Source Type: research

The tumor antigen N -glycolyl-GM3 is a human CD1d ligand capable of mediating B cell and natural killer T cell interaction
Abstract The expression of N-glycolyl-monosialodihexosyl-ganglioside (NGcGM3) in humans is restricted to cancer cells; therefore, it is a tumor antigen. There are measurable quantities of circulating anti-NGcGM3 antibodies (aNGcGM3 Abs) in human serum. Interestingly, some people have circulating Ag-specific immunoglobulins G (IgGs) that are capable of complement mediated cytotoxicity against NGcGM3 positive cells, which is relevant for tumor surveillance. In light of the chemical nature of Ag, we postulated it as a candidate ligand for CD1d. Furthermore, we hypothesize that the immune mechanism involved in the gen...
Source: Cancer Immunology, Immunotherapy - March 11, 2016 Category: Cancer & Oncology Source Type: research

Natural killer cells, ageing and cancer
Abstract Natural killer (NK) cells are key components of innate immunity and substantially contribute to anti-tumor immune responses. The role of NK cells in immune surveillance is linked to many aspects of NK cell biology, but the age of the animal being studied or the human under treatment is rarely taken into account. The solicited reviews constituting a collection of papers presented here as a “Symposium-in-Writing” on the topic of NK cells, ageing and cancer were inspired by the increasing knowledge of NK cell biology and genetics, and emerging data on their impact in the clinic (disease associati...
Source: Cancer Immunology, Immunotherapy - March 11, 2016 Category: Cancer & Oncology Source Type: research

Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells
Abstract The dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p 
Source: Cancer Immunology, Immunotherapy - March 10, 2016 Category: Cancer & Oncology Source Type: research

Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts
Abstract We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytoto...
Source: Cancer Immunology, Immunotherapy - March 10, 2016 Category: Cancer & Oncology Source Type: research

Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models
In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 9, 2016 Category: Cancer & Oncology Source Type: research

MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer
Abstract MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM–ATR) signaling and oncogene-induced PI3K–AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D–NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D liga...
Source: Cancer Immunology, Immunotherapy - March 3, 2016 Category: Cancer & Oncology Source Type: research

Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node
In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8+ T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly low...
Source: Cancer Immunology, Immunotherapy - March 2, 2016 Category: Cancer & Oncology Source Type: research

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy
Abstract A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism that prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune sys...
Source: Cancer Immunology, Immunotherapy - February 24, 2016 Category: Cancer & Oncology Source Type: research

A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17 + cell frequency
Abstract Patients with HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) have a better prognosis than patients with non-HPV-induced OPSCC. The role of the immune response in this phenomenon is yet unclear. We studied the number of T cells, regulatory T cells (Tregs), T helper 17 (Th17) cells and IL-17+ non-T cells (mainly granulocytes) in matched HPV-positive and HPV-negative OPSCC cases (n = 162). Furthermore, the production of IFN-γ and IL-17 by tumor-infiltrating T cells was analyzed. The number of tumor-infiltrating T cells and Tregs was higher in HPV-positive than HPV-negative OPSCC (p 
Source: Cancer Immunology, Immunotherapy - February 22, 2016 Category: Cancer & Oncology Source Type: research

A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor–dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2
Abstract Background Stage IV melanoma has high mortality, largely unaffected by traditional therapies. Immunotherapy including cytokine therapies and checkpoint inhibitors improves outcomes, but has significant toxicities. In this phase I/IIa trial, we investigated safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients. Methods Autologous tumor lysate and dendritic cells were fused creating dendritoma vaccines for each patient. Phase I patients were vaccinated every 3 months with IL-2 given for 5 day...
Source: Cancer Immunology, Immunotherapy - February 19, 2016 Category: Cancer & Oncology Source Type: research

Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy
Abstract Previously, we combined p19Arf (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-β, immunomodulatory cytokine) gene transfer in order to enhance cell death in a murine model of melanoma. Here, we present evidence of the immune response induced when B16 cells succumbing to death due to treatment with p19Arf and IFN-β are applied in vaccine models. Use of dying cells for prophylactic vaccination was investigated, identifying conditions for tumor-free survival. After combined p19Arf and IFN-β treatment, we observed immune rejection at the vaccine site in immune competent and nude...
Source: Cancer Immunology, Immunotherapy - February 18, 2016 Category: Cancer & Oncology Source Type: research

Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway
In this study, we focused on one of the genes (PI3KCB), identified in this genetic screen. The PI3KCB gene encodes an isoform of the catalytic subunit of PI3K called P110β. The PI3K pathway has been linked to diverse cellular functions, but has never been associated with susceptibility to NK cell activity. Gene silencing of PI3KCB resulted in increased susceptibility of several tumor cell lines to NK cell lytic activity and induced increased IFN-γ secretion by NK cells. Treatment of primary tumor cells with two different PI3K inhibitors also increased target cell susceptibility to NK cell activity. These effects...
Source: Cancer Immunology, Immunotherapy - February 16, 2016 Category: Cancer & Oncology Source Type: research

Requirement of interleukin 7 signaling for anti-tumor immune response under lymphopenic conditions in a murine lung carcinoma model
In this study, to clarify the correlation between LIP and the anti-tumor effect, LIP was inhibited with interleukin 7 (IL7) receptor blockade at various stages, and the anti-tumor effect then assessed. We confirmed that IL7 signaling at the start of LIP is crucial for the anti-tumor immune response. In contrast, continuous IL7 signaling was not required for tumor regression, although LIP of naïve CD8+ T cells is usually regulated by IL7. The expansion and migration of CTLs in lymphopenic hosts depend on IL7 signaling during the induction phase. Here, we propose that IL7 signaling and subsequent LIP of T cells have dis...
Source: Cancer Immunology, Immunotherapy - February 15, 2016 Category: Cancer & Oncology Source Type: research

Killer-cell immunoglobulin-like receptor genes and ligands and their role in hematologic malignancies
Abstract Natural killer (NK) cells are considered crucial for the elimination of emerging tumor cells. Effector NK-cell functions are controlled by interactions of inhibitory and activating killer-cell immunoglobulin-like receptors (KIRs) on NK cells with human leukocyte antigen (HLA) class I ligands on target cells. KIR and HLA are highly polymorphic genetic systems segregating independently, creating a great diversity in KIR/HLA gene profiles in different individuals. There is an increasing evidence supporting the relevance of KIR and HLA ligand gene background for the occurrence and outcome of certain cancers. ...
Source: Cancer Immunology, Immunotherapy - February 13, 2016 Category: Cancer & Oncology Source Type: research

Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity
Abstract Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRN...
Source: Cancer Immunology, Immunotherapy - February 10, 2016 Category: Cancer & Oncology Source Type: research

CD57 in human natural killer cells and T-lymphocytes
Abstract The CD57 antigen (alternatively HNK-1, LEU-7, or L2) is routinely used to identify terminally differentiated ‘senescent’ cells with reduced proliferative capacity and altered functional properties. In this article, we review current understanding of the attributes of CD57-expressing T-cells and NK cells in both health and disease and discuss how this marker can inform researchers about their likely functions in human blood and tissues in vivo. While CD57 expression on human lymphocytes indicates an inability to proliferate, these cells also display high cytotoxic potential, and CD57pos NK cell...
Source: Cancer Immunology, Immunotherapy - February 5, 2016 Category: Cancer & Oncology Source Type: research

The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity
Abstract Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-d...
Source: Cancer Immunology, Immunotherapy - February 4, 2016 Category: Cancer & Oncology Source Type: research

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors
Abstract The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV inf...
Source: Cancer Immunology, Immunotherapy - February 3, 2016 Category: Cancer & Oncology Source Type: research

Lessons learned from cancer vaccine trials and target antigen choice
Abstract A wide variety of tumor antigens have been targeted in cancer immunotherapy studies. Traditionally, the focus has been on commonly overexpressed antigens shared across many patients and/or tumor types. As the field has progressed, the identity of human tumor rejection antigens has broadened. Immunologic monitoring of clinical trials has slowly elucidated candidate biomarkers of immune response and clinical response, and conversely, of immune dysfunction and suppression. We have utilized MART-1/Melan-A in our melanoma studies and observed a high frequency of immune responses and several significant cli...
Source: Cancer Immunology, Immunotherapy - February 3, 2016 Category: Cancer & Oncology Source Type: research

Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155
Abstract T cell Ig and ITIM domain (TIGIT) is a newly identified inhibitory receptor expressed on T and natural killer (NK) cells. Cytokine-induced killer (CIK) cells express CD3 and CD56 molecules, and share functional properties with both NK and T cells. However, it remains unknown whether TIGIT is expressed in CIK cells. Here, we show that TIGIT is expressed by CIK cells and interacts with CD155. By blocking TIGIT using an anti-TIGIT functional antibody, we demonstrate that CIK cells display increased proliferation; higher cytotoxic targeting of tumor cells expressing CD155; and higher expression of interferon-...
Source: Cancer Immunology, Immunotherapy - February 3, 2016 Category: Cancer & Oncology Source Type: research

Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells
In conclusion, CatG is an essential protease for regulating MHC I molecules and thus modulation of CatG activity might present a new avenue for therapeutic intervention. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 2, 2016 Category: Cancer & Oncology Source Type: research

Exploiting IL-17-producing CD4 + and CD8 + T cells to improve cancer immunotherapy in the clinic
Abstract Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported that adoptively transferred CD4+ and CD8+ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ+Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues—such as co-stimulatory molec...
Source: Cancer Immunology, Immunotherapy - January 29, 2016 Category: Cancer & Oncology Source Type: research

Selection and expansion of natural killer cells for NK cell-based immunotherapy
Abstract Natural killer (NK) cells have been used in several clinical trials as adaptive immunotherapy. The low numbers of these cells in peripheral blood mononuclear cells (PBMC) have resulted in various approaches to preferentially expand primary NK cells from PBMC. While some clinical trials have used the addition of interleukin 2 (IL-2) to co-stimulate the expansion of purified NK cells from allogeneic donors, recent studies have shown promising results in achieving in vitro expansion of NK cells to large numbers for adoptive immunotherapy. NK cell expansion requires multiple cell signals for survival, pro...
Source: Cancer Immunology, Immunotherapy - January 25, 2016 Category: Cancer & Oncology Source Type: research

Redefining cancer immunotherapy—optimization, personalization, and new predictive biomarkers: 4th Cancer Immunotherapy and Immunomonitoring (CITIM) meeting, April 27–30, 2015, Ljubljana, Slovenia
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 25, 2016 Category: Cancer & Oncology Source Type: research

The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib
Abstract Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14+HLA-DR−/...
Source: Cancer Immunology, Immunotherapy - January 19, 2016 Category: Cancer & Oncology Source Type: research

Identification of the murine H-2D b and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes
Abstract Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT...
Source: Cancer Immunology, Immunotherapy - January 13, 2016 Category: Cancer & Oncology Source Type: research

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4 + T cells
Abstract Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly ...
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

Poly(I:C) potentiates Bacillus Calmette–Guérin immunotherapy for bladder cancer
In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread
In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8 % of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a ...
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

8th Annual Canadian Cancer Immunotherapy Consortium (CCIC) Symposium 2015—May 20–22, Vancouver, Canada
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy
In this study, we examined corresponding IL-10+ Breg responses within this patient population and demonstrate that the IL-10+ Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10+ Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10+ Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant ...
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

Acknowledgement
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 12, 2016 Category: Cancer & Oncology Source Type: research

Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients
In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 11, 2016 Category: Cancer & Oncology Source Type: research

Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery
Abstract Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, w...
Source: Cancer Immunology, Immunotherapy - January 6, 2016 Category: Cancer & Oncology Source Type: research

Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study
Abstract There is an increasing interest for monitoring circulating myeloid-derived suppressor cells (MDSCs) in cancer patients, but there are also divergences in their phenotypic definition. To overcome this obstacle, the Cancer Immunoguiding Program under the umbrella of the Association of Cancer Immunotherapy is coordinating a proficiency panel program that aims at harmonizing MDSC phenotyping. After a consultation period, a two-stage approach was designed to harmonize MDSC phenotype. In the first step, an international consortium of 23 laboratories immunophenotyped 10 putative MDSC subsets on pretested, periph...
Source: Cancer Immunology, Immunotherapy - January 4, 2016 Category: Cancer & Oncology Source Type: research

A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer
This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous w...
Source: Cancer Immunology, Immunotherapy - January 4, 2016 Category: Cancer & Oncology Source Type: research