Table of Contents

Volume 1, Issue 4

  July 2012

  Pages 407 - 577

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Abscopal but desirable: The contribution of immune responses to the efficacy of radiotherapy

Guido Kroemer and Laurence Zitvogel
Pages 407 - 408
http://dx.doi.org/10.4161/onci.20074
Abstract | Full Text | PDF

Radiotherapy applies ionizing irradiation to selected areas of the body with the scope of destroying cancer cells, either as part of curative therapies to remove a primary malignant tumor and to prevent tumor recurrence after surgery, or as part of palliative measures to avoid local advancement of bone and brain metastases. Intriguingly, radiotherapy does not only have local effects but may lead to the delayed regression of distant non-irradiated lesions. Most likely, these “abscopal” effects are mediated by the immune system.




RESEARCH PAPERS

Open Access Article

TIL therapy broadens the tumor-reactive CD8⁺ T cell compartment in melanoma patients

Pia Kvistborg and 21 others
Pages 409 - 418
http://dx.doi.org/10.4161/onci.18851
Abstract | Full Text | PDF

There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8⁺ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

Open Access Article

Combined vaccination and immunostimulatory antibodies provides durable cure of murine melanoma and induces transcriptional changes associated with positive outcome in human melanoma patients

A.J. Robert McGray, Dannie Bernard, Robin Hallett, Ryan Kelly, Mayank Jha, Caitlin Gregory, Jennifer D. Bassett, John A. Hassell, Guillaume Pare, Yonghong Wan and Jonathan L. Bramson
Pages 419 - 431
http://dx.doi.org/10.4161/onci.19534
Abstract | Full Text | PDF

We have developed a recombinant adenovirus vaccine encoding dopachrome tautomerase (rHuAd5-hDCT) that produces robust DCT-specific immunity, but only provides modest suppression of murine melanoma. In the current study, an agonist antibody against 4-1BB was shown to enhance rHuAd5-hDCT efficacy and evoke tumor regression, but most tumors ultimately relapsed. The vaccine triggered upregulation of the immune inhibitory PD-1 signaling pathway and PD-1 blockade dramatically enhanced the rHuAd5-hDCT + anti-4-1BB strategy, resulting in complete regression of growing tumors in > 70% of recipients. The impact of the combined anti-4-1BB/anti-PD-1 treatment did not manifest as a dramatic enhancement in either the magnitude or functionality of DCT-specific tumor infiltrating lymphocytes relative to either treatment alone. Rather, a synergistic enhancement in intratumoral cytokine expression was observed, suggesting that the benefit of the combined therapy was a local event within the tumor. Global transcriptional analysis revealed immunological changes within the tumor following the curative vaccination, which extended beyond the T cell compartment. We identified an immune signature of 85 genes associated with clearance of murine melanoma that correlated with improved survival outcome in two independent cohorts of human melanoma patients. Our data reinforce the concept that successful vaccination must overcome local hurdles in the tumor microenvironment that are not manifest within the periphery. Further, tumor rejection following vaccination involves more than simply T cells. Finally, the association of our immune signature with positive survival outcome in human melanoma patients suggests that similar vaccination strategies may be promising for melanoma treatment.

Open Access Article

Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients

Manuarii Manuel, Olivier Tredan, Thomas Bachelot, Gilles Clapisson, Anais Courtier, Gilles Parmentier, Tioka Rabeony, Audrey Grives, Solène Perez, Jean-François Mouret, David Perol, Sylvie Chabaud, Isabelle Ray-Coquard, Intidhar Labidi-Galy, Pierre Heudel, Jean-Yves Pierga, Christophe Caux, Jean-Yves Blay, Nicolas Pasqual and Christine Ménétrier-Caux
Pages 432 - 440
http://dx.doi.org/10.4161/onci.19545
Abstract | Full Text | PDF

Lymphopenia (< 1Giga/L) detected before initiation of chemotherapy is a predictive factor for death in metastatic solid tumors. Combinatorial T cell repertoire (TCR) diversity was investigated and tested either alone or in combination with lymphopenia as a prognostic factor at diagnosis for overall survival (OS) in metastatic breast cancer (MBC) patients. The combinatorial TCR diversity was measured by semi quantitative multi-N-plex PCR on blood samples before the initiation of the first line chemotherapy in a development (n = 66) and validation (n = 67) MBC patient cohorts. A prognostic score, combining lymphocyte count and TCR diversity was evaluated. Univariate and multivariate analyses of prognostic factors for OS were performed in both cohorts. Lymphopenia and severe restriction of TCR diversity called “divpenia” (diversity ≤ 33%) were independently associated with shorter OS. Lympho-divpenia combining lymphopenia and severe divpenia accurately identified patients with poor OS in both cohorts (7.6 and 10.6 vs 24.5 and 22.9 mo). In multivariate analysis including other prognostic clinical factors, lympho-divpenia was found to be an independent prognostic factor in the pooled cohort (p = 0.005) along with lack of HER2 and hormonal receptors expression (p = 0.011) and anemia (p = 0.009). Lympho-divpenia is a novel prognostic factor that will be used to improve quality of MBC patients’ medical care.

Open Access Article

Association of a functional Indoleamine 2,3-dioxygenase 2 genotype with specific immune responses

Tania Køllgaard, Tobias Wirenfeldt Klausen, Manja Idorn, Rikke Bæk Holmgaard, Per thor Straten and Mads Hald Andersen
Pages 441 - 447
http://dx.doi.org/10.4161/onci.19654
Abstract | Full Text | PDF

Two frequent single-nucleotide-polymorphisms (SNPs) are present in the indoleamine 2,3-dioxygenase 2 (IDO2) gene that influence its enzymatic activity. Thus, one SNP (R248W) is associated with a reduction in IDO2 catalytic activity, whereas the other SNP (Y359stop) generates a premature stop codon abolishing activity completely. In the present study, we describe the presence of a specific cellular immune response in the periphery which correlated with the functional status of the IDO2 protein. Hence, the induction of IDO2-specific T cells in peripheral blood requires the presence of a functional IDO2 protein and, consequently, is restricted to individuals that are not homozygous for the stop codon. Furthermore, we detected stronger T-cell responses in donors with the homozygous Y wild type at position 359 when compared with the heterozygous genotype. Interestingly, we found a higher number of immune responses against IDO2 in patients homozygous for the 248W giving reduction in IDO2 activity compared with the 248R. Hence, spontaneous immune responses against IDO2 seem to be correlated with reduced enzymatic activity of IDO2. The patient IDO2 genotype may well influence the outcome of IDO2-based anti-cancer vaccination.

Open Access Article

Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10

Lazar Vujanovic, Wenners Ballard, Stephen H. Thorne, Nikola L. Vujanovic and Lisa H. Butterfield
Pages 448 - 457
http://dx.doi.org/10.4161/onci.19788
Abstract | Full Text | PDF

Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56^hiCD16^- and CD56^loCD16⁺ NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.

Open Access Article

OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4⁺ T cells

Andreas A. Hombach, Johannes Heiders, Marcel Foppe, Markus Chmielewski and Hinrich Abken
Pages 458 - 466
http://dx.doi.org/10.4161/onci.19855
Abstract | Full Text | PDF

Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells recently showed remarkable anti-tumor efficacy in early phase clinical trials; self-repression of the immune response by T-cell secreted cytokines, however, is still an issue raising interest to abrogate the secretion of repressive cytokines while preserving the panel of CAR induced pro-inflammatory cytokines. We here revealed that T-cell activation by a CD28-ζ signaling CAR induced IL-10 secretion, which compromises T cell based immunity, along with the release of pro-inflammatory IFN-γ and IL-2. T cells stimulated by a ζ CAR without costimulation did not secrete IL-2 or IL-10; the latter, however, could be induced by supplementation with IL-2. Abrogation of CD28-ζ CAR induced IL-2 release by CD28 mutation did not reduce IL-10 secretion indicating that IL-10 can be induced by both a CD28 and an IL-2 mediated pathway. In contrast to the CD28-ζ CAR, a CAR with OX40 (CD134) costimulation did not induce IL-10. OX40 cosignaling by a 3rd generation CD28-ζ-OX40 CAR repressed CD28 induced IL-10 secretion but did not affect the secretion of pro-inflammatory cytokines, T-cell amplification or T-cell mediated cytolysis. IL-2 induced IL-10 was also repressed by OX40 co-signaling. OX40 moreover repressed IL-10 secretion by regulatory T cells which are strong IL-10 producers upon activation. Taken together OX40 cosignaling in CAR redirected T cell activation effectively represses IL-10 secretion which contributes to counteract self-repression and provides a rationale to explore OX40 co-signaling CARs in order to prolong a redirected T cell response.

Open Access Article

Human melanoma-specific CD8⁺ T-cells from metastases are capable of antigen-specific degranulation and cytolysis directly ex vivo

Yolanda D. Mahnke, Estelle Devevre, Petra Baumgaertner, Maurice Matter, Nathalie Rufer, Pedro Romero and Daniel E. Speiser
Pages 467 - 530
http://dx.doi.org/10.4161/onci.19856
Abstract | Full Text | PDF

The relatively low frequencies of tumor Ag-specific T-cells in PBMC and metastases from cancer patients have long precluded the analysis of their direct ex vivo cytolytic capacity. Using a new composite technique that works well with low cell numbers, we aimed at determining the functional competence of melanoma-specific CD8⁺ T-cells. A multiparameter flow cytometry based technique was applied to assess the cytolytic function, degranulation and IFNγ production by tumor Ag-specific CD8⁺ T-cells from PBMC and tumor-infiltrated lymph nodes (TILN) of melanoma patients. We found strong cytotoxicity by T-cells not only when they were isolated from PBMC but also from TILN. Cytotoxicity was observed against peptide-pulsed target cells and melanoma cells presenting the naturally processed endogenous antigen. However, unlike their PBMC-derived counterparts, T-cells from TILN produced only minimal amounts of IFNγ, while exhibiting similar levels of degranulation, revealing a critical functional dichotomy in metastatic lesions. Our finding of partial functional impairment fits well with the current knowledge that T-cells from cancer metastases are so-called exhausted, a state of T-cell hyporesponsiveness also found in chronic viral infections. The identification of responsible mechanisms in the tumor microenvironment is important for improving cancer therapies.

Open Access Article

Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo

Nai-Kong V. Cheung, Hongfen Guo, Jian Hu, Dimiter V. Tassev and Irene Y. Cheung
Pages 477 - 486
http://dx.doi.org/10.4161/onci.19864
Abstract | Full Text | PDF

Murine IgG3 anti-GD2 antibody m3F8 has shown anti-neuroblastoma activity in Phase I/II studies, where antibody-dependent cell-mediated cytotoxicity (ADCC) played a key role. Humanization of m3F8 should circumvent human anti-mouse antibody (HAMA) response and enhance its ADCC properties to reduce dosing and pain side effect. Chimeric 3F8 (ch3F8) and humanized 3F8 (hu3F8-IgG1 and hu3F8-IgG4) were produced and purified by protein A affinity chromatography. In vitro comparison was made with m3F8 and other anti-GD2 antibodies in binding, cytotoxicity, and cross-reactivity assays. In GD2 binding studies by SPR, ch3F8 and hu3F8 maintained K_D comparable to m3F8. Unlike other anti-GD2 antibodies, m3F8, ch3F8 and hu3F8 had substantially slower k_off.. Similar to m3F8, both ch3F8 and hu3F8 inhibited tumor cell growth in vitro, while cross-reactivity with other gangliosides was comparable to that of m3F8. Both peripheral blood mononuclear cell (PBMC)-ADCC and polymorphonuclear leukocytes (PMN)-ADCC of ch3F8 and hu3F8-IgG1 were more potent than m3F8. This superiority was consistently observed in ADCC assays, irrespective of donors or NK-92MI-transfected human CD16 or CD32, whereas complement mediated cytotoxicity (CMC) was reduced. As expected, hu3F8-IgG4 had near absent PBMC-ADCC and CMC. Hu3F8 and m3F8 had similar tumor-to-non tumor ratios in biodistribution studies. Anti-tumor effect against neuroblastoma xenografts was better with hu3F8-IgG1 than m3F8. In conclusion, humanizing m3F8 produced next generation anti-GD2 antibodies with substantially more potent ADCC in vitro and anti-tumor activity in vivo. By leveraging ADCC over CMC, they may be clinically more effective, while minimizing pain and HAMA side effects. A Phase I trial using hu3F8-IgG1 is ongoing.

Open Access Article

Differential activity of interferon-α8 promoter is regulated by Oct-1 and a SNP that dictates prognosis of glioma

Gary Kohanbash, Eiichi Ishikawa, Mitsugu Fujita, Maki Ikeura, Kayla McKaveney, Jianzhong Zhu, Masashi Sakaki, Saumendra N. Sarkar and Hideho Okada
Pages 487 - 492
http://dx.doi.org/10.4161/onci.19964
Abstract | Full Text | PDF

We have previously reported that the single nucleotide polymorphism (SNP) rs12553612 in IFNA8 is associated with better overall survival of glioma patients with the AA-genotype compared with patients with the AC-genotype. As rs12553612 is located in the IFNA8 promoter, we hypothesized that the A-allele allows for an enhanced IFNA8 promoter activity compared with the C-allele. Reporter assays in the human monocyte derived THP-1 cell line demonstrated a superior promoter activity of the A-allele compared with the C-allele. Electrophoretic mobility shift assays (EMSA) further demonstrated that the A-genotype specifically binds to more nuclear proteins than the C-genotype, including the transcription factor Oct-1. Further, co-transfection of plasmids encoding Oct-1 and the reporter constructs revealed that Oct-1 enhanced the promoter activity with the A- but not the C-allele. Taken together, our data demonstrate that the A-allele in the rs12553612 SNP, which is associated with better glioma patient survival, allows for IFNA8 transcription by allowing for Oct-1 binding, which is absent in patients with C allele, and suggests a molecular mechanism of IFNA8 mediated immune-surveillance of glioma progression.




REVIEWS

Open Access Article

Trial Watch: Immunostimulatory cytokines

Erika Vacchelli, Lorenzo Galluzzi, Alexander Eggermont, Jérôme Galon, Eric Tartour, Laurence Zitvogel and Guido Kroemer
Pages 493 - 506
http://dx.doi.org/10.4161/onci.20459
Abstract | Full Text | PDF

During the last two decades, a number of approaches for the activation of the immune system against cancer has been developed. These include highly specific interventions, such as monoclonal antibodies, vaccines and cell-based therapies, as well as relatively unselective strategies, such as the systemic administration of adjuvants and immunomodulatory cytokines. Cytokines constitute a huge group of proteins that, taken together, regulate not only virtually all the aspects of innate and cognate immunity, but also several other cellular and organismal functions. Cytokines operate via specific transmembrane receptors that are expressed on the plasma membrane of target cells and, depending on multiple variables, can engage autocrine, paracrine or endocrine signaling pathways. The most appropriate term for defining the cytokine network is “pleiotropic”: cytokines are produced by - and operate on - multiple, often overlapping, cell types, triggering context-depend biological outcomes as diverse as cell proliferation, chemotaxis, differentiation, inflammation, elimination of pathogens and cell death. Moreover, cytokines often induce the release of additional cytokines, thereby engaging self-amplificatory or self-inhibitory signaling cascades. In this Trial Watch, we will summarize the biological properties of cytokines and discuss the progress of ongoing clinical studies evaluating their safety and efficacy as immunomodulatory agents against cancer.

Open Access Article

MR imaging of tumor-associated macrophages

Heike Daldrup-Link and Lisa M. Coussens
Pages 507 - 509
http://dx.doi.org/10.4161/onci.19456
Abstract | Full Text | PDF

Tumor associated macrophages (TAMs) in breast cancers foster several aspects of tumor progression and metastasis, and represent a biomarker associated with an unfavorable clinical outcome. As new therapeutic agents selectively targeting leukocytes enter the clinic whose mechanism of action involves diminishing macrophage infiltration or presence in tumors, it becomes increasingly important to identify those tumors heavily infiltrated by TAMs, as well as monitoring TAM response to therapy. MR imaging with iron oxide nanoparticles enables noninvasive quantification of TAMs in tumors, and thus, provides an easily accessible ex vivo assessment of TAMs for prognosis and related treatment decisions.

Open Access Article

Hypoxia-inducible factor 1: A link between metabolism and T cell differentiation and a potential therapeutic target

Fan Pan, Joseph Barbi and Drew M. Pardoll
Pages 510 - 515
http://dx.doi.org/10.4161/onci.19457
Abstract | Full Text | PDF

Naïve T cells activated by antigen-presenting cells (APC) can be differentiated into at least four major types of T-helper (T_H) cells: T_H1, T_H2, T_H17 and inducible regulatory T cells (iTreg) based on their unique cytokine production profiles and characteristic functions.¹ T_H1 produce interferon-γ (IFNγ) and are important for protective immune responses to intracellular viral, bacterial and parasitic infection. T_H2 cells produce interleukin-4 (IL-4), IL-5, IL-23 and are critical for controlling extracellular parasites such as helminthes. T_H17 cells are responsible for expelling extracellular bacteria and fungi through secretion of IL-17a, IL-17f and IL-22.² These cells however are perhaps better known for their propensity to drive autoimmune responses. Tregs including naturally occurring regulatory T cells (nTreg) play important roles in the suppressive control of both innate and adaptive immunity in vivo.^3,4




POINTS-OF-VIEW

Open Access Article

Th17 cells have stem cell-like features and promote long-term immunity

Shuang Wei, Ende Zhao, Ilona Kryczek and Weiping Zou
Pages 516 - 519
http://dx.doi.org/10.4161/onci.19440
Abstract | Full Text | PDF

Memory T cells are one of the most effective components of anti-tumor immunity. However, limited studies on cancer patients have not addressed the phenotypic, genetic and functional heterogeneity of memory T-cell subsets in the human cancer environments. Human IL-17⁺CD4⁺ (Th17) cells are confined to memory T-cell compartment with CD45RO⁺CD62L^-CCR7^- phenotype and are enriched in CD49⁺CCR6⁺ population. Th17 cells do not express PD-1, FoxP3, KLRG-1, CD57 and IL-10, making them unlikely candidates for being functionally exhausted PD-1⁺ T cells or suppressive Foxp3⁺ or IL-10⁺ T cells or senescent CD28^-CD57⁺KLRG-1⁺ T cells. However, Th17 cells express high levels of CD95 and moderate levels of CD27. Th17 cells phenotypically resemble terminally differentiated memory T cells. Interestingly, Th17 cells possess polyfunctional cytokine profile, and have stem cell-like features. Th17 stemness may be partially controlled by signaling pathways of hypoxia inducible factor HIF1α, Notch and Bcl. The stem cell-like character of Th17 cells is an important decisive factor for Th17 cell biology.

Open Access Article

A genetic inference on cancer immune responsiveness

Ena Wang, Lorenzo Uccellini and Francesco M. Marincola
Pages 520 - 525
http://dx.doi.org/10.4161/onci.19531
Abstract | Full Text | PDF

A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness.




AUTHOR'S VIEWS

Open Access Article

Immune mediated mechanisms of melanocyte destruction: Paving the way for efficient immunotherapeutic strategies against melanoma

Reinhart Speeckaert, Nanja van Geel, Jo Lambert, Barbara Boone, Ines Chevolet, Mireille Van Gele, Marijn M. Speeckaert and Lieve Brochez
Pages 526 - 528
http://dx.doi.org/10.4161/onci.19403
Abstract | Full Text | PDF

Insights into immune reactions against benign and malignant melanocytes may help the development of more efficient immunotherapeutic treatments for melanoma. The interplay between an active systemic antitumor immunity and a responsive local tumor environment is crucial to achieve effective clinical responses. Increasing evidence confirms this strategy can lead to an adequate and durable immunosurveillance of melanocytes.

Open Access Article

Colon cancer cells produce immunoregulatory glucocorticoids

Daniel Sidler, Pietro Renzulli, Christina Schnoz, Barbara Berger, Sabine Schneider-Jakob, Christa Flück, Daniel Inderbitzin, Nadia Corazza, Daniel Candinas and Thomas Brunner
Pages 529 - 530
http://dx.doi.org/10.4161/onci.19459
Abstract | Full Text | PDF

Expression or release of immunosuppressive molecules may protect tumor cells from the recognition and destruction by the immune system. New findings indicate that colorectal tumors produce immunoregulatory glucocorticoids and thereby suppress immune cell activation. The nuclear receptor LRH-1 plays a critical role in the regulation of colorectal tumor proliferation and glucocorticoid synthesis.

Open Access Article

Tumor infiltration by chemokine receptor 7 (CCR7)⁺ T-lymphocytes is a favorable prognostic factor in metastatic colorectal cancer

Pierpaolo Correale, Maria Saveria Rotundo, Cirino Botta, Maria Teresa Del Vecchio, Pierfrancesco Tassone and Pierosandro Tagliaferri
Pages 531 - 532
http://dx.doi.org/10.4161/onci.19404
Abstract | Full Text | PDF

The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall survival.

Open Access Article

IRF-1 is critical for IFNγ mediated immune surveillance

Antje Ksienzyk, Berit Neumann and Andrea Kröger
Pages 533 - 534
http://dx.doi.org/10.4161/onci.19405
Abstract | Full Text | PDF

We recently described that IRF-1 is important for IFNγ mediated immune surveillance in metastasis. Despite the upregulation of MHC Class I in tumor cells, IRF-1 leads to a NK cell-dependent elimination of tumor cells. This mechanism is independent on inhibitory receptors and cytotoxic granules but dependent on DNAM-1.

Open Access Article

Tumor suppressors control ULBP2, an innate surface ligand of the lymphocyte immune receptor NKG2D

Anja Heinemann and Annette Paschen
Pages 535 - 536
http://dx.doi.org/10.4161/onci.19406
Abstract | Full Text | PDF

The activating receptor NKG2D, expressed on different innate and adaptive cytotoxic lymphocytes, has been demonstrated to play an important role in anti-tumor immunity. Now evidence is provided that tumor suppressors control expression of its ligand ULBP2 supporting the role of this receptor-ligand system as an innate barrier against tumor development.

Open Access Article

Interleukin 21 impairs tumor immunosurveillance of colitis-associated colorectal cancer

Rebecca Kesselring, Dominik Jauch and Stefan Fichtner-Feigl
Pages 537 - 538
http://dx.doi.org/10.4161/onci.19407
Abstract | Full Text | PDF

The pathogenesis of colitis-associated colorectal cancer is strongly influenced by immune cells, cytokines and other immune mediators present in the inflamed colon. Current research has emerged that T helper cell associated cytokines play a prominent role in tumor growth. In our recent manuscript we have revealed that the Th17 associated cytokine IL-21 prominently influences tumor development and immunosurveillance of colitis-associated colorectal cancer.

Open Access Article

Engineering hematopoietic stem cells to create melanoma specific CTL

Dimitrios Vatakis
Pages 539 - 540
http://dx.doi.org/10.4161/onci.19408
Abstract | Full Text | PDF

Using a humanized mouse model, we developed melanoma specific CD8 T cells from genetically modified human hematopoietic stem cells (hHSC). The transgenic T cells were functional both in vivo and ex vivo, effectively limiting and clearing tumor growth. Finally, the transduced hHSC stably populated the bone marrow.

Open Access Article

A novel facet of tumor suppression by p53: Induction of tumor immunogenicity

Hai Li, Tadepally Lakshmikanth, Ennio Carbone and Galina Selivanova
Pages 541 - 543
http://dx.doi.org/10.4161/onci.19409
Abstract | Full Text | PDF

Pharmacological reactivation of the p53 tumor suppressor is a promising strategy for anti-cancer therapy due to its high potential to elicit apoptosis or growth arrest in cancer cells. Recently we uncovered the mechanism of activation of the innate immune response by p53 upon its activation by small molecules.

Open Access Article

CTLA-4 blockade synergizes with cryoablation to mediate tumor rejection

Rebecca Waitz, Marcella Fassò and James P. Allison
Pages 544 - 546
http://dx.doi.org/10.4161/onci.19442
Abstract | Full Text | PDF

We report that cryoablation of primary tumors synergizes with anti-CTLA-4 treatment to mediate rejection of secondary tumors in the TRAMP mouse model of prostate cancer. T cells, in particular CD8⁺ T cells specific for the TRAMP antigen SPAS-1, were enriched in both secondary tumors and spleens of combination-treated mice.

Open Access Article

Pro-survival signaling via CD27 costimulation drives effective CAR T-cell therapy

De-Gang Song and Daniel J. Powell, Jr.
Pages 547 - 549
http://dx.doi.org/10.4161/onci.19458
Abstract | Full Text | PDF

The impact of CD27 costimulation on human T lymphocyte effector function and memory formation has been limited to evaluations using in vitro cell culture systems and observations from the clinic. We therefore investigated whether CD27 signaling augments antigen redirected human T-cell survival, expansion and function in vitro and in vivo.

Open Access Article

Identification of a G-CSF-Granulocytic MDSC axis that promotes tumor progression

Scott I. Abrams and Jeremy D. Waight
Pages 550 - 551
http://dx.doi.org/10.4161/onci.19334
Abstract | Full Text | PDF

Myeloid-derived suppressor cells (MDSC) induced during neoplasia display potent pro-tumorigenic activities. Tumor-derived factors influence MDSC development, yielding monocytic and granulocytic subsets. In contrast to monocytic MDSC, little is known about how granulocytic MDSC develop. We demonstrated that tumor-derived G-CSF drives granulocytic MDSC formation, thus providing new insights into myeloid-tumor biology.

Open Access Article

β-endorphin neuron transplantation: A possible novel therapy for cancer prevention

Changqing Zhang and Dipak K. Sarkar
Pages 552 - 554
http://dx.doi.org/10.4161/onci.19335
Abstract | Full Text | PDF

We summarize here our new discovery that the endogenous opioid peptide β-endorphin (BEP), by virtue of reducing body stress and maintaining active immune system, as well as, balancing the levels of pro-inflammatory and anti-inflammatory cytokines, destroys tumor cells and stops them from being transformed into metastatic cancer cells.

Open Access Article

Innate predisposition to immune escape in follicular lymphoma cells

Pauline Gravelle, Christine Jean, Wilfried Valleron, Guy Laurent and Jean-Jacques Fournié
Pages 555 - 556
http://dx.doi.org/10.4161/onci.19365
Abstract | Full Text | PDF

Tumor-intrinsic immuno-resistance is a prerequisite for emergence of follicular lymphomas. Here we show that in vitro, such cells are more resistant to immune cytolysis when grown as follicle-mimicking tridimensional aggregates than when grown as cell suspensions. So in patients, this innate adaptation to tumor immunity might precede its selective pressure.

Open Access Article

The wolf in sheep’s clothing: Platelet-derived “pseudo self” impairs cancer cell “missing self” recognition by NK cells

Theresa Placke, Hans-Georg Kopp and Helmut Rainer Salih
Pages 557 - 559
http://dx.doi.org/10.4161/onci.19367
Abstract | Full Text | PDF

Metastasis is strongly inhibited in thrombocytopenic mice. This phenotype is reversed by NK cell depletion which indicates that platelets may facilitate tumor progression and metastasis by interfering with NK cell immunosurveillance. Understanding the underlying mechanisms may help us to reinforce anti-tumor immunity and NK-based immunotherapy in cancer patients.

Open Access Article

Immuno-targeting of pancreatic cancer stem cells: A new therapeutic strategy against a devastating disease?

Michele Cioffi and Christopher Heeschen
Pages 560 - 562
http://dx.doi.org/10.4161/onci.19368
Abstract | Full Text | PDF

Pancreatic cancer is a highly aggressive and deadly disease harboring a distinct population of cancer stem cells (CSC) that is not affected by conventional therapies. A new therapeutic approach using the EpCAM/CD3-bispecific antibody MT110 is capable of activating and redirecting cytotoxic T cells to eliminate primary human pancreatic cancer stem cells, which resulted in long-term survival of preclinical xenografts models.

Open Access Article

Chemoimmunotherapy as long-term maintenance therapy for cancer

Nejat K. Egilmez, Jamie L. Harden and Rachael B. Rowswell-Turner
Pages 563 - 565
http://dx.doi.org/10.4161/onci.19369
Abstract | Full Text | PDF

Homeostatic immune regulatory mechanisms can mediate premature termination of therapy-induced antitumor T-effector cell responses. Administration of cyclophosphamide (CY) prior to intratumoral IL-12 and GM-CSF delivery blocked post-treatment T-suppressor cell rebound via elimination of the pre-existing T-suppressor cell pool, allowed repeated activation of antitumor cytotoxic T-cells and resulted in the cure of advanced spontaneous tumors.

Open Access Article

Cytotoxic and antigen presenting functions of T helper-1-activated dendritic cells

Nicolas Larmonier, Bernard Bonnotte and Emmanuel Katsanis
Pages 566 - 568
http://dx.doi.org/10.4161/onci.19370
Abstract | Full Text | PDF

Although primarily defined by their cardinal antigen-presenting function, dendritic cells (DCs) are also equipped with cytotoxic properties. We have recently reported that DCs activated by IFNγ-secreting Th-1 lymphocytes can kill cancer cells and subsequently present the acquired tumor-derived antigens to T lymphocytes both in vitro and in vivo.

Open Access Article

Inhibition of CXCLs/CXCR2 axis in the tumor microenvironment might be a potent therapeutics for pancreatic cancer

Hideaki Ijichi
Pages 569 - 571
http://dx.doi.org/10.4161/onci.19402
Abstract | Full Text | PDF

Pancreatic cancer is characterized by expanded stroma with marked fibrosis. In Ijichi et al., we show that inhibiting CXCR2 disrupts tumor-stromal interactions and improves survival of a genetically-engineered mouse model recapitulating human pancreatic cancer. Targeting CXCLs/CXCR2 axis in the tumor microenvironment might be a potent therapeutic strategy for pancreatic cancer.

Open Access Article

A novel mechanism for cancer cells to evade immune attack by NK cells: The interaction between NKp44 and proliferating cell nuclear antigen

Benyamin Rosental, Uzi Hadad, Michael Brusilovsky, Kerry S. Campbell and Angel Porgador
Pages 572 - 574
http://dx.doi.org/10.4161/onci.19366
Abstract | Full Text | PDF

We recently reported proliferating cell nuclear antigen (PCNA) as a ligand for the NK cell activating receptor, NKp44, which unexpectedly triggers inhibition. The recognition of nuclear proteins such as PCNA, by related NK cell receptors has been reported. Widespread upregulation of PCNA in tumor cells may therefore promote immune evasion.

Open Access Article

Know thy enemy: Why are tumor-infiltrating regulatory T cells so deleterious?

Andrea Facciabene, Stephen Santoro and George Coukos
Pages 575 - 577
http://dx.doi.org/10.4161/onci.19401
Abstract | Full Text | PDF

We recently described hypoxia as one of the leading mechanism for the recruitment of regulatory T cells (Treg) through CCL28 chemokine in ovarian cancer. Treg promote progression of cancer through tumor-specific immune paralysis but also reprogramming of angiogenesis. We review these mechanisms and discuss the challenges and opportunities for therapy targeting Treg.