Table of Contents

Volume 1, Issue 1

  January/February 2012

  Pages 1 - 125

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

OncoImmunology: a new journal at the frontier between oncology and immunology

Laurence Zitvogel and Guido Kroemer
Pages 1 - 2
http://dx.doi.org/10.4161/onci.1.1.17645
Full Text | PDF




OBITUARY

Open Access Article

The fabulous legacy of a Nobel Prize Laureate: Ralph M. Steinman, 1943-2011

Laurence Zitvogel, Miriam Merad and Guido Kroemer
Pages 3 - 8
http://dx.doi.org/10.4161/onci.1.1.18538
Abstract | Full Text | PDF

The Nobel Prize in Physiology or Medecine 2011 was awarded to Ralph M. Steinman, Jules A. Hoffman and Bruce A. Beutler for the discovery of essential elements of innate immunity, in particular dendritic cells (DCs) and toll-like receptors (TLRs). Antigens become immunogenic and capable of triggering an adaptive immune response involving antigen-specific, MHC- restricted effector T cells, only if they are captured and presented by “accessory” cells. In 1972, Ralph M. Steinman and Zanvil Cohn identified in lymphoid tissues, cells with treelike, arborescent morphology that they named “dendritic cells” (DC) (from the greek word “tree” for tree, δένδρον) with a superior ability to induce alloreactive T cell proliferation in vitro (1978) and to stimulate the rejection of kidney allotransplants in rodents (1982). Thirty years after their discovery, DCare now known to play a seminal role in bridging innate and adaptive immunity, In addition DC are being used in numerous clinical studies all over the world to increase immunity to infectious or tumor-associated antigens. This effort involved the contribution of an international network of basicand clinical scientists spearheaded by Ralph M. Steinman to defineappropriate culture conditions to generate ex vivo DC from circulating or bone marrow precursors, to definefunctionally distinct DC subsets, to identifytheir maturation pathways including those relying on the stimulation of TLRs, and finally to develop DC based-vaccines to immunize patients infected with HIV or affected by cancer. Here, we will detail the history of DC and outline the therapeutic implications of Ralph M. Steinman’s seminal discovery.




RESEARCH PAPERS

Open Access Article

Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response

Romulus Breban, Aurelie Bisiaux, Claire Biot, Cyrill Rentsch, Philippe Bousso and Matthew L. Albert
Pages 9 - 17
http://dx.doi.org/10.4161/onci.1.1.17884
Abstract | PDF

Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50–70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidence suggests that BCG-activated neutrophils possess anti-tumor potential. Moreover, weekly BCG treatment results in a prime-boost pattern with massive influx of innate immune cells (107–108 PMN/ml urine). Calibrating in vivo data, we estimate that the number of neutrophil degranulations per instillation is approximately 106–107, more than sufficient to potentially eliminate ~106 residual tumor cells. Furthermore, neutrophils, as well as other innate effector cells are not selective in their targeting—thus surrounding cells may be influenced by degranulation and / or cytokine production. To establish if these observed conditions could account for clinically effective tumor immunity, we built a mathematical model reflecting the early events and tissue conditioning in patients undergoing BCG therapy. The model incorporates key features of tumor growth, BCG instillations and the observed prime / boost pattern of the innate immune response. Model calibration established that each innate effector cell must kill 90–95 bystander cells for achieving the expected 50–70% clinical response. This prediction was evaluated both empirically and experimentally and found to vastly exceed the capacity of the innate immune system. We therefore conclude that the innate immune system alone is unable to eliminate the tumor cells. We infer that other aspects of the immune response (e.g., antigen-specific lymphocytes) decisively contribute to the success of BCG immunotherapy.

Open Access Article

Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection

Anders Rosén, Ann-Charlotte Bergh, Peter Gogok, Chamilly Evaldsson, Anna Lanemo Myhrinder, Eva Hellqvist, Abu Rasul, Magnus Björkholm, Mattias Jansson, Larry Mansouri, Anquan Liu, Bin Tean Teh, Richard Rosenquist and Eva Klein
Pages 18 - 27
http://dx.doi.org/10.4161/onci.1.1.18400
Abstract | Full Text | PDF

Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1–2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16–1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.




REVIEWS

Open Access Article

Trial Watch: Monoclonal antibodies in cancer therapy

Lorenzo Galluzzi, Erika Vacchelli, Wolf Hervé Fridman, Jérôme Galon, Catherine Sautès-Fridman, Eric Tartour, Jessica Zucman-Rossi, Laurence Zitvogel and Guido Kroemer
Pages 28 - 37
http://dx.doi.org/10.4161/onci.1.1.17938
Abstract | PDF

Since the advent of hybridoma technology, dating back to 1975, monoclonal antibodies have become an irreplaceable diagnostic and therapeutic tool for a wide array of human diseases. During the last 15 years, several monoclonal antibodies (mAbs) have been approved by FDA for cancer therapy. These mAbs are designed to (1) activate the immune system against tumor cells, (2) inhibit cancer cell-intrinsic signaling pathways, (3) bring toxins in the close proximity of cancer cells, or (4) interfere with the tumor-stroma interaction. More recently, major efforts have been made for the development of immunostimulatory mAbs that either enhance cancer-directed immune responses or limit tumor- (or therapy-) driven immunosuppression. Some of these antibodies, which are thought to facilitate tumor eradication by initiating or sustaining a tumor-specific immune response, have already entered clinical trials. In this Trial Watch, we will review and discuss the clinical progress of the most important mAbs that are have entered clinical trials after January 2008.

Open Access Article

NK cells sense tumors, course of disease and treatments: Consequences for NK-based therapies

Giulia Fregni, Aurélie Perier, Marie-Françoise Avril and Anne Caignard
Pages 38 - 47
http://dx.doi.org/10.4161/onci.1.1.18312
Abstract | Full Text | PDF

The recent findings on NK activation indicate that these cells are important antitumor effectors. NK cells participate in the graft-vs.-leukemia effect to control the relapse in leukemic patients transplanted with allogeneic hematopoietic stem cells. In various tumors, correlation between NK cell infiltrates and prognosis were reported. However, tumor-infiltrating NK cells are yet poorly characterized. We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

Open Access Article

Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities

Angela D. Pardee and Lisa H. Butterfield
Pages 48 - 55
http://dx.doi.org/10.4161/onci.1.1.18344
Abstract | Full Text | PDF

Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.




MINI-REVIEWS

Open Access Article

Investigation of a new tumor-associated glycosylated antigen as target for dendritic cell vaccination in pancreatic cancer

Evelyne Béraud, Aurélie Collignon, Cécile Franceschi, Daniel Olive, Dominique Lombardo and Eric Mas
Pages 56 - 61
http://dx.doi.org/10.4161/onci.1.1.18459
Abstract | Full Text | PDF

Glycoproteins, as valuable targets for dendritic cell (DC)-vaccination in cancers, remain an open question. Glycosylated structures, which are aberrantly modified during cancerisation, impact positively or negatively on glycoprotein immunogenicity. Here is presented an oncofetal glycovariant of bile-salt-dependent-lipase, expressed on human tumoral pancreas and efficiently processed by DC’s, inducing T-lymphocyte activation.

Open Access Article

The local immunological microenvironment in colorectal cancer as a prognostic factor for treatment decisions in the clinic: The way ahead

Niels Halama, Inka Zoernig, Niels Grabe and Dirk Jaeger
Pages 62 - 66
http://dx.doi.org/10.4161/onci.1.1.18460
Abstract | Full Text | PDF

Analysis of the local immunological microenvironment in colorectal cancer lesions yielded prognostic markers. Harnessing these insights for clinical application however requires the use of sophisticated technology and algorithms, especially the robust and reproducible quantification of immune cells. These technologies are available and will allow individualized treatment decisions beyond the current standard.

Open Access Article

CD73 promotes tumor growth and metastasis

Bin Zhang
Pages 67 - 70
http://dx.doi.org/10.4161/onci.1.1.18068
Abstract | Full Text | PDF

Our recent data and that of others demonstrate that both tumor and host CD73-generated adenosine promote tumor growth and metastasis in a multifactorial manner. Results with small molecule inhibitors or monoclonal antibodies against CD73 in multiple tumor models suggest that CD73 is a previously unappreciated important target for effective cancer therapy.

Open Access Article

EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers?

Brian P. Pollack
Pages 71 - 74
http://dx.doi.org/10.4161/onci.1.1.18073
Abstract | PDF

A recent study from our laboratory demonstrated that epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) augment the expression of class I and class II MHC molecules. This finding provides an additional mechanism through which EGFRIs may exert anti-tumor effects and supports the notion that EGFRIs may influence adaptive immune responses by altering immune gene expression.




AUTHOR'S VIEWS

Open Access Article

High expression of CD20+ lymphocytes in soft tissue sarcomas is a positive prognostic indicator

Sveinung W. Sorbye, Thomas Kilvaer, Andrej Valkov, Tom Donnem, Eivind Smeland, Khalid Al-Shibli, Roy M. Bremnes and Lill-Tove Busund
Pages 75 - 77
http://dx.doi.org/10.4161/onci.1.1.17825
Abstract | PDF

The immune status is important in cancer patients. Tissue microarrays from 249 patients with soft tissue sarcomas were constructed. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. High density of CD20+ lymphocytes is an independent positive prognostic indicator for these patients.

Open Access Article

Cancer cells use exosomes as tools to manipulate immunity and the microenvironment

Aled Clayton
Pages 78 - 80
http://dx.doi.org/10.4161/onci.1.1.17826
Abstract | PDF

Exosomes are small vesicles secreted in relative abundance by cancer cells, which may prove useful as disease markers. However, exosomes also exhibit potent functions; modulating the behavior of immune- and other cells. Bridging our understanding of their molecular phenotype and functional mechanisms will provide key insight into their importance in cancer.

Open Access Article

ERAAP modulation: A possible novel strategy for cancer immunotherapy?

Doriana Fruci, Franco Locatelli and Loredana Cifaldi
Pages 81 - 82
http://dx.doi.org/10.4161/onci.1.1.17828
Abstract | PDF

Recent findings demonstrate that loss of ERAAP, an endoplasmic reticulum aminopeptidase involved in antigen processing, plays a key role in stimulating anti-tumor innate and adaptive immune responses. We show that MHC class I molecules produced in the absence of ERAAP retain their capability of presenting antigens to CD8+ T cells, but not of inhibiting NK cells.

Open Access Article

To respond or not to respond to CD40 agonism: That is the prediction

Xiaoyan Shi and David Dornan
Pages 83 - 85
http://dx.doi.org/10.4161/onci.1.1.17827
Abstract | PDF

In the context of the clinical development of a CD40-stimulatory monoclonal antibody for the treatment of B-cell cancers, a tumor mRNA-based gene signature reflecting CD40 signaling pathway activation status was identified that could be used to predict responding and non-responding patients with diffuse large B cell lymphoma (DLBCL).

Open Access Article

PD-L1 co-stimulation, ligand-induced TCR down-modulation and anti-tumor immunotherapy

Katarzyna Karwacz, Frederick Arce, Christopher Bricogne, Grazyna Kochan and David Escors
Pages 86 - 88
http://dx.doi.org/10.4161/onci.1.1.17824
Abstract | PDF

PD-1 engagement on the surface of effector T cells strongly suppresses their cytotoxic function, which constitutes a major obstacle for T cell-mediated anti-tumor activities. Surprisingly, PD-1 is strongly upregulated in T cells, engaging its ligand PD-L1 during antigen presentation. However, our recent published data may provide an explanation for this apparent contradiction.

Open Access Article

Cross-talk within the tumor microenvironment mediates Th2-type inflammation in pancreatic cancer

Maria Pia Protti and Lucia De Monte
Pages 89 - 91
http://dx.doi.org/10.4161/onci.1.1.17939
Abstract | PDF

Th2-type inflammation has been proposed to facilitate tumor growth. In De Monte et al. (J Exp Med 208:469-478, 2011) we identify in pancreatic cancer a complex cytokine/chemokine cross-talk within the tumor microenvironment mediating Th2 immune-deviation and show that the ratio of Th2/Th1 tumor infiltrating lymphocytes is an independent predictive marker of patients survival.

Open Access Article

Infiltrating CTLs are bothered by HLA-E on tumors

Marloes J.M. Gooden and Thorbald van Hall
Pages 92 - 93
http://dx.doi.org/10.4161/onci.1.1.17961
Abstract | PDF

We recently described the upregulation of HLA-E in ovarian and cervical cancers. Instead of interacting with natural killer cells, HLA-E appeared to inhibit intratumoral cytotoxic T lymphocytes (CTL) via the receptor CD94/NKG2A. Strikingly, the survival benefit of intraepithelial infiltrating CTL was lost in those cancers with high HLA-E expression.

Open Access Article

Non-apoptotic routes to defeat cancer

Jennifer L. Guerriero, Dara Ditsworth and Wei-Xing Zong
Pages 94 - 96
http://dx.doi.org/10.4161/onci.1.1.17885
Abstract | PDF

The mechanism of tumor cell death after treatment with DNA alkylating agents in vivo previously remained largely unknown. We demonstrate that tumor regression after chemotherapy occurs via sporadic necrosis and relies on activation of innate immunity in a manner dependent on high mobility group box 1 protein (HMGB1).

Open Access Article

Immunochemotherapy against colon cancer by gene transfer of interleukin-12 in combination with oxaliplatin

Ruben Hernandez-Alcoceba and Pedro Berraondo
Pages 97 - 99
http://dx.doi.org/10.4161/onci.1.1.17930
Abstract | PDF

Using a murine model of liver metastases, we found that oxaliplatin can enhance the immunostimulatory effect of interleukin-12 delivered by an adenoviral vector. A shift toward a favorable immune microenvironment was observed in tumors, with a relative increase in CD8+ T cells vs. T regulatory and myeloid-derived suppressor cells.

Open Access Article

Targeting platelet function to improve drug delivery

Mélanie Demers and Denisa D. Wagner
Pages 100 - 102
http://dx.doi.org/10.4161/onci.1.1.17962
Abstract | PDF

Thrombocytopenia-induced tumor hemorrhage improves drug delivery to tumors. This phenomenon presents a new way to increase drug efficacy with minimal side effects. Combining anti-platelet treatment with therapeutic drugs may help us in the search for more effective ways to fight cancer.

Open Access Article

Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy

Pascale Hubert and Sebastian Amigorena
Pages 103 - 105
http://dx.doi.org/10.4161/onci.1.1.17963
Abstract | PDF

Antibody-dependent cell cytotoxicity (ADCC) is critical in monoclonal antibody (mAb)-mediated cancer therapy. We recently showed that a tumor-specific mAb in combination with cyclophosphamide inhibited tumor cell growth and induced ADCC-synapses between tumor and effector cells in vivo, opening perspectives to enhance anti-tumor responses by manipulating the immune system.

Open Access Article

CCR5 in cancer immunotherapy: More than an “attractive” receptor for T cells

Alicia González-Martín, Emilia Mira and Santos Mañes
Pages 106 - 108
http://dx.doi.org/10.4161/onci.1.1.17995
Abstract | PDF

Despite intensive study, the role of CCR5 in cancer remains elusive. We showed that CCR5 expression by both CD4+ and CD8+ T cells is necessary to boost anti-tumor responses by optimizing helper-dependent CD8+ T cell priming. Our findings could have implications for cancer treatment in patients with defective CCR5 expression.

Open Access Article

Dysregulation of anti-tumor immunity by the matrix metalloproteinase-2

Emmanuelle Godefroy and Nina Bhardwaj
Pages 109 - 111
http://dx.doi.org/10.4161/onci.1.1.17994
Abstract | PDF

The matrix metalloproteinase-2 (MMP-2), overexpressed in most cancers, induces TH2 polarization by conditioning dendritic cells to over-express OX40L and downregulate IL-12p70 through the degradation of the type-I IFN receptor IFNAR1. Elucidating mechanisms underlying detrimental tumor-associated type-2 responses represent a crucial step in designing effective immune therapies to treat cancer patients.

Open Access Article

Annexin A2 is a new antigenic target for pancreatic cancer immunotherapy

Lei Zheng and Elizabeth M. Jaffee
Pages 112 - 114
http://dx.doi.org/10.4161/onci.1.1.18017
Abstract | PDF

In our recent publication (Zheng et al., PLoS ONE) we described the identification of annexin A2 as a new pancreatic cancer associated tumor antigen. Its involvement in pancreatic cancer progression and metastases supports its role as an antigenic target for the development of both therapeutic antibody and T cell immunotherapy.

Open Access Article

A matched couple: Combining kinase inhibitors with immunotherapy for cancer treatment

Qun Jiang, Jonathan M. Weiss and Robert H. Wiltrout
Pages 115 - 117
http://dx.doi.org/10.4161/onci.1.1.18036
Abstract | PDF

Small-molecule kinase inhibitors targeting oncogenic signaling pathways have been explored as cancer therapeutic agents due to their strong anti-tumor activity and manageable toxicity. Accumulating evidence shows that many kinase inhibitors also profoundly modulate immune cell functions, suggesting they may be promising candidates for combination with immunotherapeutic agents for the improved treatment of cancer.

Open Access Article

Colon cancer eradication after chemoimmunotherapy is associated with intratumoral emergence of proinflammatory myeloid cells

José Medina-Echeverz and Pedro Berraondo
Pages 118 - 120
http://dx.doi.org/10.4161/onci.1.1.18049
Abstract | PDF

Interleukin-12 immune stimulation lacks efficacy in established solid tumor models. Disruption of tumor microenvironment homeostasis by low-dose cyclophosphamide prior to interleukin-12 gene therapy led to CD8+ T cell-driven established tumor rejection. This only takes place when inflammatory myeloid cells infiltrate the tumor bed, and is crucial for the latter antitumor response.

Open Access Article

Chemoimmunomodulation of MDSCs as a novel strategy for cancer therapy

Julie Djeu and Sheng Wei
Pages 121 - 122
http://dx.doi.org/10.4161/onci.1.1.18074
Abstract | PDF

Tumor-induced myeloid-derived suppressor cells (MDSCs) are a critical barrier to effective immunotherapy of cancer. We identified that Docetaxel and a natural compound, Icariin, can target MDSCs with preferential apoptosis of M2 cells and polarization of the surviving cells towards M1 cells. Such strategic targeting of MDSCs restored T cell function accompanied by tumor retardation in vivo.

Open Access Article

Cytotoxic T lymphocytes: Sniping cancer stem cells

Yoshihiko Hirohashi, Toshihiko Torigoe, Satoko Inoda, Rena Morita, Vitaly Kochin and Noriyuki Sato
Pages 123 - 125
http://dx.doi.org/10.4161/onci.1.1.18075
Abstract | PDF

Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are characterized as a small population of cancer cells that have high tumor-initiating ability. CSCs/CICs are resistant to several cancer therapies, and eradication of CSCs/CICs is essential to cure cancer. How can we eradicate CSCs/CICs? Cytotoxic T lymphocytes (CTLs) might be a promising answer.