Evolution of MHC-based technologies used for detection of antigen-responsive T cells
AbstractT cell-mediated recognition of peptide-major histocompatibility complex (pMHC) class I and II molecules is crucial for the control of intracellular pathogens and cancer, as well as for stimulation and maintenance of efficient cytotoxic responses. Such interactions may also play a role in the development of autoimmune diseases. Novel insights into this mechanism are crucial to understanding disease development and establishing new treatment strategies. MHC multimers have been used for detection of antigen-responsive T cells since the first report by Altman et al. showed that tetramerization of pMHC class I molecules...
Source: Cancer Immunology, Immunotherapy - March 17, 2017 Category: Cancer & Oncology Source Type: research

Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms ’ tumor 1 protein
AbstractSeveral types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms ’ tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can b e administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinantBifidobacterium longum displaying WT1 protein.B. longum 420 was ...
Source: Cancer Immunology, Immunotherapy - March 15, 2017 Category: Cancer & Oncology Source Type: research

Expression patterns of programmed death-ligand 1 in esophageal adenocarcinomas: comparison between primary tumors and metastases
AbstractExpression analysis of programmed death-ligand 1 (PD-L1) may be helpful in guiding clinical decisions for immune checkpoint inhibition therapy, but testing by immunohistochemistry may be hampered by heterogeneous staining patterns within tumors and expression changes during metastatic course. PD-L1 expression (clone SP142) was investigated in esophageal adenocarcinomas using tissue microarrays (TMA) from 112 primary resected tumors, preoperative biopsies and full slide sections from a subset of these cases (n = 24), corresponding lymph node (n = 55) and distant metastases (n =&thi...
Source: Cancer Immunology, Immunotherapy - March 13, 2017 Category: Cancer & Oncology Source Type: research

The PD-L1/PD-1 pathway promotes dysfunction, but not “exhaustion”, in tumor-responding T cells from pleural effusions in lung cancer patients
AbstractMalignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts. PD-L1 was up-regulated in lung cancer cell lines upon t...
Source: Cancer Immunology, Immunotherapy - March 13, 2017 Category: Cancer & Oncology Source Type: research

In memory of Professor Enrico Mihich: Editor-in-Chief of Cancer Immunology, Immunotherapy 1982 –2012
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 11, 2017 Category: Cancer & Oncology Source Type: research

Phenotype and function of tumor-associated neutrophils and their subsets in early-stage human lung cancer
AbstractNeutrophils accumulate in many types of human and murine tumors and represent a significant portion of tumor-infiltrating myeloid cells. Our current understanding of the role of neutrophils in tumor development has depended primarily on murine models of cancer. However, there are crucial species differences in the evolution of tumors, genetic diversity, immune and inflammatory responses, and intrinsic biology of neutrophils that might have a profound impact on the tumor development and function of neutrophils in mouse versus human tumors. To date, the majority of experimental approaches to study neutrophils in canc...
Source: Cancer Immunology, Immunotherapy - March 10, 2017 Category: Cancer & Oncology Source Type: research

Myeloid cells in circulation and tumor microenvironment of breast cancer patients
AbstractPathological conditions including cancers lead to accumulation of a morphological mixture of highly immunosuppressive cells termed as myeloid-derived suppressor cells (MDSC). The lack of conclusive markers to identify human MDSC, due to their heterogeneous nature and close phenotypical and functional proximity with other cell subsets, made it challenging to identify these cells. Nevertheless, expansion of MDSC has been reported in periphery and tumor microenvironment of various cancers. The majority of studies on breast cancers were performed on murine models and hence limited literature is available on the relatio...
Source: Cancer Immunology, Immunotherapy - March 10, 2017 Category: Cancer & Oncology Source Type: research

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis
AbstractAdoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2R γ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in ...
Source: Cancer Immunology, Immunotherapy - March 9, 2017 Category: Cancer & Oncology Source Type: research

TANTIGEN: a comprehensive database of tumor T cell antigens
AbstractTumor T cell antigens are both diagnostically and therapeutically valuable molecules. A large number of new peptides are examined as potential tumor epitopes each year, yet there is no infrastructure for storing and accessing the results of these experiments. We have retroactively cataloged more than 1000 tumor peptides from 368 different proteins, and implemented a web-accessible infrastructure for storing and accessing these experimental results. All peptides in TANTIGEN are labeled as one of the four categories: (1) peptides measured in vitro to bind the HLA, but not reported to elicit either in vivo or in vitro...
Source: Cancer Immunology, Immunotherapy - March 9, 2017 Category: Cancer & Oncology Source Type: research

Mechanisms of efficacy in cancer immunotherapy: 14th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 10 –12, 2016
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 1, 2017 Category: Cancer & Oncology Source Type: research

Novel B7-H4-mediated crosstalk between human non-Hodgkin lymphoma cells and tumor-associated macrophages leads to immune evasion via secretion of IL-6 and IL-10
In conclusion, this study shows that NHL-expressed B7-H4 is an important immunosuppressive factor that inhibits host anti-tumor immunity to NHL. Targeting tumor-expresse d B7-H4 may thus provide a new treatment strategy for NHL patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 28, 2017 Category: Cancer & Oncology Source Type: research

Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site
We describe here our finding th at a CD45+ CD11bmid Ly6C+ cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce M φ accumulation in STING-deficient mice. Depletion of CD8+ T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the M φ using clodronate lipo...
Source: Cancer Immunology, Immunotherapy - February 27, 2017 Category: Cancer & Oncology Source Type: research

Interleukin 21 inhibits cancer-mediated FOXP3 induction in na ïve human CD4 T cells
AbstractIL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in na ïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, a...
Source: Cancer Immunology, Immunotherapy - February 27, 2017 Category: Cancer & Oncology Source Type: research

Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors
AbstractTalimogene laherparepvec is a first-in-class intralesional oncolytic immunotherapy. In a recent Phase III trial (OPTiM), talimogene laherparepvec significantly improved durable response rate compared with subcutaneous granulocyte –macrophage colony-stimulating factor (GM-CSF). Overall response rate was also higher in the talimogene laherparepvec arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma. Talimogene laherparepvec was well tolerated, with the majority (89%) of adverse events being grade 1 or 2. Preclinical studies have shown that talimogene la...
Source: Cancer Immunology, Immunotherapy - February 25, 2017 Category: Cancer & Oncology Source Type: research

Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma
AbstractV-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint regulatory molecule, suppresses T cell mediated immune responses. The aim of the present study was to profile the immunological expression, clinical significance and correlation of VISTA in human oral squamous cell carcinoma (OSCC). Human tissue microarrays, containing 165 primary OSCCs, 48 oral epithelial dysplasias and 43 normal oral mucosae, were applied to investigate the expression levels of VISTA, CD8, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death ligand 1 (PD-L1), PI3K α p110, IL13Rα2, phospho-...
Source: Cancer Immunology, Immunotherapy - February 24, 2017 Category: Cancer & Oncology Source Type: research

FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice
AbstractTumors evade immune recognition and destruction in many ways including the creation of an immune-suppressive tumor microenvironment (TME). Dendritic cells (DC) that infiltrate the TME are tolerogenic, and suppress effector T cells and anti-tumor activity. Previous reports demonstrated that a key regulator of tolerance in DC is the transcription factor FOXO3. Gender disparity has been studied in cancer in relation to incidence, aggressiveness, and prognosis. Few studies have touched on the importance in relation to impact on the immune system. In the current study, we show that there are significant differences in t...
Source: Cancer Immunology, Immunotherapy - February 22, 2017 Category: Cancer & Oncology Source Type: research

Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1
AbstractRegulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers. We further demonstrate that decreased ...
Source: Cancer Immunology, Immunotherapy - February 21, 2017 Category: Cancer & Oncology Source Type: research

Mechanisms overseeing myeloid-derived suppressor cell production in neoplastic disease
AbstractPerturbations in myeloid cell differentiation are common in neoplasia, culminating in immature populations known as myeloid-derived suppressor cells (MDSCs). MDSCs favor tumor progression due to their ability to suppress host immunity or promote invasion and metastasis. They are thought to originate from the bone marrow as a result of exposure to stromal- or circulating tumor-derived factors (TDFs). Although great interest has been placed on understanding how MDSCs function, less is known regarding how MDSCs develop at a transcriptional level. Our work explores the premise that MDSCs arise because cancer cells, thr...
Source: Cancer Immunology, Immunotherapy - February 21, 2017 Category: Cancer & Oncology Source Type: research

Upregulation of thioredoxin-1 in activated human NK cells confers increased tolerance to oxidative stress
AbstractAdoptive transfer of immune cells, such as T lymphocytes and NK cells, has potential to control cancer growth. However, this can be counteracted by immune escape mechanisms within the tumor microenvironment, including those mediated by reactive oxygen species (ROS). Here, we determined the levels of anti-oxidant molecules in NK cells and their capacity to overcome ROS-induced immune suppression. We investigated the effect of H2O2 on resting NK cells, IL-2-activated NK cells and NK cells expanded by coculture with the K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand (K562...
Source: Cancer Immunology, Immunotherapy - February 21, 2017 Category: Cancer & Oncology Source Type: research

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities
AbstractImmunotherapies emerged as an alternative for cancer treatment, yet their clinical efficacies are still limited, especially in case of solid tumors. Myeloid immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), are often hijacked by tumors and become pivotal inhibitors of antitumor immunity. Immunosuppressive functions of tumor-associated myeloid cells result from the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor with well-defined tumorigenic and tolerogenic roles in human cancers. To overcome challenges in the development of pharmacological...
Source: Cancer Immunology, Immunotherapy - February 18, 2017 Category: Cancer & Oncology Source Type: research

Dendritic cell rehab: new strategies to unleash therapeutic immunity in ovarian cancer
AbstractImmune-based therapies that induce remarkable and durable responses against melanoma and lung cancer have unfortunately demonstrated limited success in ovarian cancer patients. This is likely due to the exceptional immunoregulatory nature of ovarian tumors, which employ numerous strategies to effectively suppress anti-tumor immunity. Here, we summarize a decade of research indicating that ovarian cancers possess an exquisite capacity to subvert the activity of host dendritic cells (DCs) as a key mechanism to impede the development and maintenance of protective T cell-based immune responses. Identifying, understandi...
Source: Cancer Immunology, Immunotherapy - February 18, 2017 Category: Cancer & Oncology Source Type: research

PD-1 and PD-L1 antibodies in cancer: current status and future directions
AbstractImmunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironm...
Source: Cancer Immunology, Immunotherapy - February 17, 2017 Category: Cancer & Oncology Source Type: research

Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis
We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received cortic osteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enteroco litis remission, w...
Source: Cancer Immunology, Immunotherapy - February 15, 2017 Category: Cancer & Oncology Source Type: research

Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy
ConclusionsIn this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 14, 2017 Category: Cancer & Oncology Source Type: research

Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF- βR II and NKG2D
AbstractThe capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor- β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellu...
Source: Cancer Immunology, Immunotherapy - February 9, 2017 Category: Cancer & Oncology Source Type: research

Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF- α
AbstractPD-L1 is an immune checkpoint protein that has emerged as a major signaling molecule involved with tumor escape from T cell immune responses. Studies have shown that intra-tumoral expression of PD-L1 can inhibit antitumor immune responses. However, it has recently been shown that expression of PD-L1 on myeloid cells from the tumor is a stronger indicator of prognosis than tumor cell PD-L1 expression. Therefore, it is important to understand the factors that govern the regulation of PD-L1 expression on tumor-infiltrating myeloid cells. We found that immature bone marrow monocytes in tumor-bearing mice had low levels...
Source: Cancer Immunology, Immunotherapy - February 9, 2017 Category: Cancer & Oncology Source Type: research

Differences in the frequencies of HLA-class I and II alleles between German patients with renal cell carcinoma and healthy controls
AbstractThe human leukocyte antigen (HLA) system is a major part of the human immune system and has an impact on tumor initiation, tumor progression, and immunosurveillance. Renal cell carcinoma tumors are considered to be immunogenic. Therefore, we studied the allele frequencies of four gene loci (HLA-A, -B, -C, and HLA-DR) in a cohort of German renal cell carcinoma (RCC) patients and in healthy controls. HLA-A-C were determined using serological methods, whereas HLA-C12, C14, C16, C18, and HLA-DR were characterized through the use of standard molecular biological methods. The occurrence of the HLA-C*12 allele was signifi...
Source: Cancer Immunology, Immunotherapy - February 9, 2017 Category: Cancer & Oncology Source Type: research

Acknowledgement
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 9, 2017 Category: Cancer & Oncology Source Type: research

Inclusion of BLIMP-1 + effector regulatory T cells improves the Immunoscore in a cohort of New Zealand colorectal cancer patients: a pilot study
AbstractAnalysis of tumour-infiltrating T cells in colorectal cancer can predict disease-free survival. The Immunoscore, obtained by quantifying tumour-infiltrating CD3+ and CD8+ T cells, may improve current staging. Effector regulatory T cells are a potently suppressive subset in mice and, while present in human colorectal cancer, their role in patient outcome is unknown. Immunofluorescence was used to analyse immune cell infiltrates in patients with early (stage II) colorectal cancer with (n = 13) and without (n = 19) recurrent disease. CD3 and CD8 were used for the Immunoscore; FOXP3, BLIMP-1...
Source: Cancer Immunology, Immunotherapy - January 23, 2017 Category: Cancer & Oncology Source Type: research

Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients
AbstractMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that are increased in the peripheral blood of cancer patients and limit productive immune responses against tumors. Immunosuppressive MDSCs are well characterized in murine splenic tissue and are found at higher frequencies in spleens of tumor-bearing mice. However, no studies have yet analyzed these cells in parallel human spleens. We hypothesized that MDSCs would be increased in the spleens of human cancer patients, similar to tumor-bearing mice. We compared the frequency and function of MDSC subsets in dissociated human sple...
Source: Cancer Immunology, Immunotherapy - January 20, 2017 Category: Cancer & Oncology Source Type: research

Intralesional treatment of metastatic melanoma: a review of therapeutic options
AbstractIntralesional therapy of melanoma patients with locally advanced metastatic disease is attracting increasing interest, not least due to its ability to lead to both direct tumor cell killing and the stimulation of both a local and a systemic immune response. An obvious pre-requisite for this type of approach is the presence of accessible metastases that are amenable to direct injection with the therapeutic agent of interest. Patients who present with these characteristics belong to stages IIIB/C or IV of the disease. Surgical resection with intention to cure is the standard of care for patients with limited tumor bu...
Source: Cancer Immunology, Immunotherapy - January 11, 2017 Category: Cancer & Oncology Source Type: research

Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model
AbstractB7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tu...
Source: Cancer Immunology, Immunotherapy - January 10, 2017 Category: Cancer & Oncology Source Type: research

Rejection versus escape: the tumor MHC dilemma
Abstract Most tumor cells derive from MHC-I-positive normal counterparts and remain positive at early stages of tumor development. T lymphocytes can infiltrate tumor tissue, recognize and destroy MHC class I (MHC-I)-positive cancer cells ( “permissive” phase I). Later, MHC-I-negative tumor cell variants resistant to T-cell killing emerge. During this process, tumors first acquire a heterogeneous MHC-I expression pattern and finally become uniformly MHC-I-negative. This stage (phase II) represents a “non-permissive” encapsulate d structure with tumor nodes surrounded by fibrous tissue containing diff...
Source: Cancer Immunology, Immunotherapy - December 31, 2016 Category: Cancer & Oncology Source Type: research

Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma
AbstractAdoptive immunotherapy leveraging chimeric antigen receptor-modified T (CAR-T) cells holds great promise for the treatment of cancer. However, tumor-associated antigens often have low expression levels in normal tissues, which can cause on-target, off-tumor toxicity. Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma (HCC) xenografts in mice. However, it remains unknown whether on-target, off-tumor toxicity can occur. Therefore, we proposed that dual-targeted CAR-T cells co-expressing glypican-3 (GPC3) and asialoglycoprotein receptor 1 (ASGR1) (a liver tissue-specific prot...
Source: Cancer Immunology, Immunotherapy - December 29, 2016 Category: Cancer & Oncology Source Type: research

Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice
AbstractCytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure. To address these difficulties, a new approac...
Source: Cancer Immunology, Immunotherapy - December 23, 2016 Category: Cancer & Oncology Source Type: research

The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients
AbstractSmall molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from ...
Source: Cancer Immunology, Immunotherapy - December 23, 2016 Category: Cancer & Oncology Source Type: research

Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma —safety and efficacy in a phase II study
AbstractTreatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3  mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients w...
Source: Cancer Immunology, Immunotherapy - December 22, 2016 Category: Cancer & Oncology Source Type: research

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer
AbstractTh1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN- γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T ce...
Source: Cancer Immunology, Immunotherapy - December 22, 2016 Category: Cancer & Oncology Source Type: research

T cell receptor gene recombinations in human tumor specimen exome files: detection of T cell receptor- β VDJ recombinations associates with a favorable oncologic outcome for bladder cancer
AbstractUnderstanding tumor-resident T cells is important for cancer prognosis and treatment options. Conventional, solid tumor specimen exome files can be searched directly for recombined T cell receptor (TcR)- α segments; RNASeq files can include TcR-β VDJ recombinations. To learn whether there are medically relevant uses of exome-based detection of TcR V(D)J recombinations in the tumor microenvironment, we searched cancer genome atlas and Moffitt Cancer Center, tumor specimen exome files for TcR-β, Tc R-γ, and TcR-δ recombinations, for bladder and stomach cancer. We found that bladder cancer ...
Source: Cancer Immunology, Immunotherapy - December 19, 2016 Category: Cancer & Oncology Source Type: research

Bio-HMGB1 from breast cancer contributes to M-MDSC differentiation from bone marrow progenitor cells and facilitates conversion of monocytes into MDSC-like cells
AbstractMyeloid-derived suppressor cells (MDSC) constitute the major cell population that regulates immune responses. They are known to accumulate in tumors, chronic inflammatory and autoimmune diseases. Previous data indicate that high mobility group box 1(HMGB1) facilitates MDSC differentiation from bone marrow, suppresses NK cells, CD4+ and CD8+ T cells and is involved in cancer development. However, it remains unclear what potential mechanisms of HMGB1 facilitate MDSC differentiation. In the present work, we clearly demonstrate that HMGB1 secreted by cancer cells is N-glycosylated at Asn37, which facilitates monocytic ...
Source: Cancer Immunology, Immunotherapy - December 16, 2016 Category: Cancer & Oncology Source Type: research

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma
ConclusionsTreatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 9, 2016 Category: Cancer & Oncology Source Type: research

Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy
AbstractTumor endothelial marker 1 (TEM1) has been identified as a novel surface marker upregulated on the blood vessels and stroma in many solid tumors. We previously isolated a novel single-chain variable fragment (scFv) 78 against TEM1 from a yeast display scFv library. Here, we evaluated the potential applications of scFv78 as a tool for tumor molecular imaging, immunotoxin-based therapy and nanotherapy. Epitope mapping, three-dimensional structure docking and affinity measurements indicated that scFv78 could bind to both human and murine TEM1, with equivalent affinity, at a well-conserved conformational epitope. The r...
Source: Cancer Immunology, Immunotherapy - December 8, 2016 Category: Cancer & Oncology Source Type: research

Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro
AbstractMyeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells that suppress anti-tumor immunity. MDSC are increased in tumor-bearing hosts; thus, depletion of MDSC may enhance anti-tumor immunity. Histone deacetylase inhibitors (HDACi) are chemical agents that are primarily used against hematologic malignancies. The ability of these agents to modulate anticancer immunity has recently been extensively studied. However, the effect of HDACi on MDSC has remained largely unexplored. In the present study, we provide the first demonstration that HDACi treatment decreases MDSC accum...
Source: Cancer Immunology, Immunotherapy - December 3, 2016 Category: Cancer & Oncology Source Type: research

Prognostic significance of the lymphocyte-to-monocyte ratio and the tumor-infiltrating lymphocyte to tumor-associated macrophage ratio in patients with stage T3N0M0 esophageal squamous cell carcinoma
ConclusionsThe prognostic significance of the CD45RO/CD68 ratio was higher than that of the LMR. The CD45RO/CD68 ratio is a useful independent prognostic marker in patients with pT3N0M0 ESCC who have undergone complete resection without neoadjuvant therapy. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 3, 2016 Category: Cancer & Oncology Source Type: research

Preventive DNA vaccination against CEA-expressing tumors with anti-idiotypic scFv6.C4 DNA in CEA-expressing transgenic mice
AbstractCarcinoembryonic antigen (CEA) is expressed during embryonic life and in low level during adult life. Consequently, the CEA is recognized by the immune system as a self-antigen and thus CEA-expressing tumors are tolerated. Previously, we constructed a single chain variable fragment using the 6.C4 (scFv6.C4) hybridoma cell line, which gave rise to antibodies able to recognize CEA when C57/Bl6 mice were immunized. Here, the scFv6.C4 ability to prevent the CEA-expressing tumor growth was assessed  in CEA-expressing transgenic mice CEA2682. CEA2682 mice immunized with the scFv6.C4 expressing plasmid vector (uP/PS-...
Source: Cancer Immunology, Immunotherapy - December 2, 2016 Category: Cancer & Oncology Source Type: research

Targeting of the WT1 91 –138 fragment to human dendritic cells improves leukemia-specific T-cell responses providing an alternative approach to WT1-based vaccination
In conclusion, our approach identifies four WT1 peptide-antibody fusion proteins with sufficient production and introduces an alternative vaccine that could be easily translated into clinical practice to improve WT1-directed antileukemia immune responses after allo-HSCT. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 28, 2016 Category: Cancer & Oncology Source Type: research

A polymorphism in the promoter region of PD-L1 serves as a binding-site for SP1 and is associated with PD-L1 overexpression and increased occurrence of gastric cancer
In this study, we found a polymorphism rs10815225 in thePD-L1 promoter region was significantly associated with the occurrence of gastric cancer. The GG homozygous frequency was higher in the cancer patients than that in the precancerous lesions, which was higher than that in the health controls. This polymorphism locates in the binding-site of Sp1 transcription factor (SP1). The expression level ofPD-L1 mRNA in the GG homozygous cancer patients was apparently higher than that in the GC heterozygotes. Luciferase reporter results showed that SP1 bonded to rs10815225 G-allelic PD-L1 promoter instead of C-allelic. Upregulatio...
Source: Cancer Immunology, Immunotherapy - November 26, 2016 Category: Cancer & Oncology Source Type: research

Selective effect of cytokine-induced killer cells on survival of patients with early-stage melanoma
In conclusion, CIK cells combined with conventional treatments may prolong the survival of early-stage melanoma patients and improve the quality of life for some advanced cases in a safe way. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 26, 2016 Category: Cancer & Oncology Source Type: research

Cytokine-induced killer cells hunt individual cancer cells in droves in a mouse model
Abstract Cytotoxicity of cytokine-induced killer (CIK) cells depends mainly on their encounters with target cells, but how many CIK cells are required to kill an individual cancer cell is unknown. Here we used time-lapse imaging to quantify the critical effector cell number required to kill an individual target cell. CIK cells killed MHC-I-negative and MHC-I-positive cancer cells, but natural killer (NK) cells destroyed MHC-I-negative cells only. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 ...
Source: Cancer Immunology, Immunotherapy - November 25, 2016 Category: Cancer & Oncology Source Type: research

Schwann cells: a new player in the tumor microenvironment
AbstractCancerous cells must cooperate with the surrounding stroma and non-malignant cells within the microenvironment to support the growth and invasion of the tumor. The nervous system is a component of every organ system of the body, and therefore, is invariably at the front line of the tumor invasion. Due to the complexity of the nervous system physiology, this review separately discusses the contributions of the central and peripheral nervous systems to the tumorigenesis and tumor progression. We further focus the discussion on the evidence that Schwann cells aid in tumor growth and invasion. Schwann cells, a largely ...
Source: Cancer Immunology, Immunotherapy - November 24, 2016 Category: Cancer & Oncology Source Type: research