Table of Contents

Volume 2, Issue 1

  January 2013

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 Issue Catalogue (MARC XML)

EDITORIAL

Open Access Article

Victories and deceptions in tumor immunology: Stimuvax^®

Guido Kroemer, Laurence Zitvogel and Lorenzo Galluzzi
eLocation ID: e23687
http://dx.doi.org/10.4161/onci.23687
Full Text | PDF




RESEARCH PAPERS

Open Access Article

Human MHC Class I-restricted high avidity CD4⁺ T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo

Shao-An Xue, Liquan Gao, Maryam Ahmadi, Sara Ghorashian, Rafael D Barros, Constandina Pospori, Angelika Holler, Graham Wright, Sharyn Thomas, Max Topp, Emma C Morris and Hans J. Stauss
eLocation ID: e22590
http://dx.doi.org/10.4161/onci.22590
Abstract | Full Text | PDF

In this study, we generated human MHC Class I-restricted CD4⁺ T cells specific for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), two herpesviridae associated with lymphoma, nasopharyngeal carcinoma and medulloblastoma, respectively. Retroviral transfer of virus-specific, HLA-A2-restricted TCR-coding genes generated CD4⁺ T cells that recognized HLA-A2/peptide multimers and produced cytokines when stimulated with MHC Class II-deficient cells presenting the relevant viral peptides in the context of HLA-A2. Peptide titration revealed that CD4⁺ T cells had a 10-fold lower avidity than CD8⁺ T cells expressing the same TCR. The impaired avidity of CD4⁺ T cells was corrected by simultaneously transferring TCR- and CD8-coding genes. The CD8 co-receptor did not alter the cytokine signature of CD4⁺ T cells, which remained distinct from that of CD8⁺ T cells. Using the xenogeneic NOD/SCID mouse model, we demonstrated that human CD4⁺ T cells expressing a specific TCR and CD8 can confer efficient protection against the growth of tumors expressing the EBV or CMV antigens recognized by the TCR. In summary, we describe a robust approach for generating therapeutic CD4⁺ T cells capable of providing MHC Class I-restricted immunity against MHC Class II-negative tumors in vivo.

Open Access Article

Targeting EpCAM (CD326) for immunotherapy in hepatoblastoma

Sorin Armeanu-Ebinger, Alexander Hoh, Julia Wenz and Joerg Fuchs
eLocation ID: e22620
http://dx.doi.org/10.4161/onci.22620
Abstract | Full Text | PDF

Hepatoblastoma (HB) is the most common liver cancer in children. Recurrence of HB after chemotherapy and surgery is frequent among high-risk patients and is associated with chemoresistance. Immunotherapy may improve poor treatment outcomes in HB patients. Cytotoxic leukocytes of the innate and adaptive immune system including different populations of cytotoxic T cells play a major role in fighting developing tumors. In this setting, monoclonal antibodies may be employed to specifically direct immune responses toward tumor cells. We addressed this issue by using humanized antibodies that recognize the cell surface molecule EpCAM (CD326, overexpressed in hepatic tumor cells) to enhance immune responses against HB. EpCAM was constantly expressed on HB cells and its expression was independent of previous therapy based on the DNA-damaging agent cisplatin. Co-culture assays performed with two well-described HB cell lines and tumor tissue cultures demonstrated that tumor cell lysis by γδ T cells can be dramatically augmented by applying EpCAM-specific monoclonal antibodies. These data emphasize the value of antitumor immune responses and encourage adapting immunotherapeutic regimens to improve the outcome of high risk HB.

Open Access Article

A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE₂-mediated immunosuppression and inhibits breast cancer metastasis

Xinrong Ma, Dawn Holt, Namita Kundu, Jocelyn Reader, Olga Goloubeva, Yukinori Take and Amy M. Fulton
eLocation ID: e22647
http://dx.doi.org/10.4161/onci.22647
Abstract | Full Text | PDF

Cyclooxygenase-2 is frequently upregulated in epithelial tumors and contributes to poor outcomes in multiple malignancies. The COX-2 product prostaglandin E₂ (PGE₂) promotes tumor growth and metastasis by acting on a family of four G protein-coupled receptors (EP1–4). Using a novel small molecule EP4 antagonist (RQ-15986) and a syngeneic murine model of metastatic breast cancer, we determined the effect of EP4 blockade on innate immunity and tumor biology. Natural killer (NK)-cell functions are markedly depressed in mice bearing murine mammary tumor 66.1 or 410.4 cells owing to the actions of PGE₂ on NK cell EP4 receptors. The EP4 agonist PGE₁-OH inhibits NK functions in vitro, and this negative regulation is blocked by RQ-15986. Likewise, the treatment of tumor-bearing mice with RQ-15986 completely protected NK cells from the immunosuppressive effects of the tumor microenvironment in vivo. RQ-15986 also has direct effects on EP4 expressed by tumor cells, inhibiting the PGE₂-mediated activation of adenylate cyclase and blocking PGE₂-induced tumor cell migration. The pretreatment of tumor cells with a non-cytotoxic concentration of RQ-15986 inhibited lung colonization, a beneficial effect that was lost in mice depleted of NK cells. The oral administration of RQ-15986 inhibited the growth of tumor cells implanted into mammary glands and their spontaneous metastatic colonization to the lungs, resulting in improved survival. Our findings reveal that EP4 antagonism prevents tumor-mediated NK-cell immunosuppression and demonstrates the anti-metastatic activity of a novel EP4 antagonist. These observations support the investigation of EP4 antagonists in clinical trials.

Open Access Article

Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer

Lana E. Kandalaft, Daniel J. Powell, Jr., Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Marnix Bosch, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, Carl H. June and George Coukos
eLocation ID: e22664
http://dx.doi.org/10.4161/onci.22664
Abstract | Full Text | PDF

Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 10⁹ autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8⁺ lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes.

Open Access Article

Vemurafenib enhances MHC induction in BRAF^V600E homozygous melanoma cells

Bishu Sapkota, Charles E. Hill and Brian P. Pollack
eLocation ID: e22890
http://dx.doi.org/10.4161/onci.22890
Abstract | Full Text | PDF

To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAF^V600E mutational status and BRAF^V600E inhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAF^V600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAF^V600E has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAF^V600E mutation. These findings suggest that BRAF^V600E activity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAF^V600E mutation, which is not routinely assessed in melanoma patients.

Open Access Article

An independent endocytic pathway stimulates different monocyte subsets by the a2 N-terminus domain of vacuolar-ATPase

Christina Kwong, Alice Gilman-Sachs and Kenneth Beaman
eLocation ID: e22978
http://dx.doi.org/10.4161/onci.22978
Abstract | Full Text | PDF

The vacuolar ATPase (V-ATPase) plays an important role in tumor progression and metastases. A novel peptide from the a2 isoform of V-ATPase called a2NTD has been shown to exert an immunoregulatory role in the tumor microenvironment by controlling the maturation of monocytes toward a tumor-associated macrophage phenotype. Our data indicate that a2NTD binds to the surface of monocytes. a2NTD was preferentially endocytosed by pro-inflammatory monocytes bearing a CD14⁺⁺CD16⁺ phenotype, which is associated with the monocyte-to-macrophage maturation process. Both a2NTD binding and internalization led to production of the pro-inflammatory cytokines interleukin (IL)-1α and IL-1β by CD14⁺⁺CD16^- (classical) and CD14⁺⁺CD16⁺ (intermediate) monocytes. a2NTD was internalized via a macropinocytosis mechanism utilizing scavenger receptors. However, the inhibition of a2NTD endocytosis did not reduce cytokine production by monocytes. This points to the existence of two receptors that respond to a2NTD: scavengers receptors that mediate cellular uptake and an hitherto unidentified receptor stimulating the production of inflammatory cytokines. Both of these monocyte receptors may be important in generating the localized inflammation that is often required to promote tumor growth and hence may constitute novel targets for the development of anticancer drugs.

Open Access Article

Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors

Robert H. Vonderheide, Jennifer M. Burg, Rosemarie Mick, Jennifer A. Trosko, Dongguang Li, M. Naveed Shaik, Anthony W. Tolcher and Omid Hamid
eLocation ID: e23033
http://dx.doi.org/10.4161/onci.23033
Abstract | Full Text | PDF

CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 (Schedule A) or day 8 (Schedule B), repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.




BRIEF REPORT

Open Access Article

Intravaginal live attenuated Salmonella increase local antitumor vaccine-specific CD8⁺ T cells

Loane Decrausaz, Christelle Pythoud, Sonia Domingos-Pereira, Laurent Derré, Patrice Jichlinski and Denise Nardelli-Haefliger
eLocation ID: e22944
http://dx.doi.org/10.4161/onci.22944
Abstract | Full Text | PDF

We have recently reported that the intravaginal instillation of synthetic Toll-like receptor 3 (TLR3) or TLR9 agonists after a subcutaneous vaccination against human papillomavirus E7 highly increases (~5-fold) the number of vaccine-specific CD8⁺ T cells in the genital mucosa of mice, without affecting E7-specific systemic responses. Here, we show that the instillation of live attenuated Salmonella enterica serovar Typhimurium similarly, though more efficiently (~15- fold), increases both E7-specific and total CD8⁺ T cells in the genital mucosa. Cancer immunotherapeutic strategies combining vaccination with local immunostimulation with live bacteria deserve further investigations.




REVIEWS

Open Access Article

Trial watch: Monoclonal antibodies in cancer therapy

Erika Vacchelli, Alexander Eggermont, Jérôme Galon, Catherine Sautès-Fridman, Laurence Zitvogel, Guido Kroemer and Lorenzo Galluzzi
eLocation ID: e22789
http://dx.doi.org/10.4161/onci.22789
Abstract | Full Text | PDF

During the past 20 years, dozens—if not hundreds—of monoclonal antibodies have been developed and characterized for their capacity to mediate antineoplastic effects, either as they activate/enhance tumor-specific immune responses, either as they interrupt cancer cell-intrinsic signal transduction cascades, either as they specifically delivery toxins to malignant cells or as they block the tumor-stroma interaction. Such an intense research effort has lead to the approval by FDA of no less than 14 distinct molecules for use in humans affected by hematological or solid malignancies. In the inaugural issue of OncoImmunology, we briefly described the scientific rationale behind the use of monoclonal antibodies in cancer therapy and discussed recent, ongoing clinical studies investigating the safety and efficacy of this approach in patients. Here, we summarize the latest developments in this exciting area of clinical research, focusing on high impact studies that have been published during the last 15 months and clinical trials launched in the same period to investigate the therapeutic profile of promising, yet hitherto investigational, monoclonal antibodies.

Open Access Article

Establishing the role of tyrosine kinase 2 in cancer

Caroline Übel, Stephanie Mousset, Denis Trufa, Horia Sirbu and Susetta Finotto
eLocation ID: e22840
http://dx.doi.org/10.4161/onci.22840
Abstract | Full Text | PDF

Tyrosine kinase 2 (TYK2) is a member of the Janus family of non-receptor tyrosine kinases involved in cytokine signaling. TYK2 deficiency is associated with increased susceptibility to mycobacterial and viral infections, hyper IgE syndrome as well as with allergic asthma. However the precise role of TYK2 in oncogenesis and tumor progression is not clear yet. Tyk2-deficient mice are prone to develop tumors because they lack efficient cytotoxic CD8⁺ T-cell antitumor responses as a result of deficient Type I interferon signaling. However, as TYK2 functions downstream of growth factor receptors that are often hyperactivated in cancer, inhibiting TYK2 might also have beneficial effects for cancer treatment.

Open Access Article

T-cell modulatory properties of CD5 and its role in antitumor immune responses

Mouna Tabbekh, M’Barka Mokrani-Hammani, Georges Bismuth and Fathia Mami-Chouaib
eLocation ID: e22841
http://dx.doi.org/10.4161/onci.22841
Abstract | Full Text | PDF

The destruction of tumor cells by the immune system is under the control of positive and negative receptors that tightly regulate T-cell effector functions. The T-cell receptor (TCR) inhibitory molecule CD5 critically contributes to the regulation of antitumor immune responses. Indeed, the modulation of CD5 within the tumor microenvironment corresponds to a strategy adopted by tumor-specific cytotoxic T lymphocytes (CTLs) to optimize their cytotoxic and cytokine secretion functions. In this review, we provide insights into the immunobiology of CD5 and its role in regulating antitumor CD8 T-cell responses, and suggest the possibility of targeting CD5 to improve the efficacy of current immunotherapeutic approaches against cancer.

Open Access Article

Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation

Adam J. Adler and Anthony T. Vella
eLocation ID: e22837
http://dx.doi.org/10.4161/onci.22837
Abstract | Full Text | PDF

The ability of T cells to recognize a vast array of antigens enables them to destroy tumor cells while inflicting minimal collateral damage. Nevertheless, tumor antigens often are a form of self-antigen, and thus tumor immunity can be dampened by tolerance mechanisms that evolved to prevent autoimmunity. Since tolerance can be induced by steady-state antigen-presenting cells that provide insufficient co-stimulation, the exogenous administration of co-stimulatory agonists can favor the expansion and tumoricidal functions of tumor-specific T cells. Agonists of the co-stimulatory tumor necrosis factor receptor (TNFR) family members CD134 and CD137 exert antitumor activity in mice, and as monotherapies have exhibited encouraging results in clinical trials. This review focuses on how the dual administration of CD134 and CD137 agonists synergistically boosts T-cell priming and elaborates a multi-pronged antitumor immune response, as well as how such dual co-stimulation might be translated into effective anticancer therapies.




POINT-OF-VIEW

Open Access Article

Tumor cell recognition by γδ T lymphocytes: T-cell receptor vs. NK-cell receptors

Daniel V. Correia, Antonio C. Lopes and Bruno Silva-Santos
eLocation ID: e22892
http://dx.doi.org/10.4161/onci.22892
Abstract | Full Text | PDF

The dissection of the molecular mechanisms underlying tumor-cell recognition by γδ T-cells is crucial to improve their performance in cancer immunotherapy. Here, we discuss the controversy around the relative contributions of the γδ T-cell receptor (TCR) and natural killer receptors (NKRs) to tumor-cell targeting by γδ T cells.




AUTHOR'S VIEWS

Open Access Article

Improving the outcome of adoptive cell transfer by targeting tumor escape

Karen M. Kaluza and Richard Vile
eLocation ID: e22059
http://dx.doi.org/10.4161/onci.22059
Abstract | Full Text | PDF

Adoptive T-cell transfer is among the most promising immunotherapies against cancer. To continue increasing the potential of this therapy, our studies focus on the inhibition of tumor recurrence. Recently, we have demonstrated several ways in which combination therapies involving multiple T-cell populations and immunostimulatory chemotherapy can enhance long-term survival.

Open Access Article

The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors

Matteo Bellone, Arianna Calcinotto, Paola Filipazzi, Angelo De Milito, Stefano Fais and Licia Rivoltini
eLocation ID: e22058
http://dx.doi.org/10.4161/onci.22058
Abstract | Full Text | PDF

We have recently reported that lowering the pH to values that are frequently detected in tumors causes reversible anergy in both human and mouse CD8⁺ T lymphocytes in vitro. The same occurs in vivo, in the tumor microenvironment and the administration of proton pump inhibitors, which buffer tumor acidity, can revert T-cell anergy and increase the efficacy of immunotherapy.

Open Access Article

A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect

Linda F. Thompson, Hiroki Tsukamoto, Petya Chernogorova and Robert Zeiser
eLocation ID: e22107
http://dx.doi.org/10.4161/onci.22107
Abstract | Full Text | PDF

The utility of allogeneic stem cell transplantation for treating hematologic malignancies is enhanced by the graft vs. tumor (GvT) effect, but limited by graft vs. host disease (GvHD). Studies involving the inhibition of CD73 by genetic or pharmacologic means suggest that the levels of CD73-generated adenosine may be manipulated to control GvHD, while maintaining the GvT effect.

Open Access Article

Immunogenic tumor cell death induced by chemoradiotherapy in a clinical setting

Koji Kono and Kousaku Mimura
eLocation ID: e22197
http://dx.doi.org/10.4161/onci.22197
Abstract | Full Text | PDF

Although it has been shown in murine models that chemoradiotherapy may induce immunogenic tumor cell death, which could trigger T-cell immunity upon the released of high-mobility group box 1 protein (HMGB1), whether this also occurs in clinical settings remains unclear. Here, we discuss tumor-antigen specific T-cell responses in esophageal cancer patients receiving chemoradiotherapy. Our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses and that the release of HMGB1 is related to clinical outcome.

Open Access Article

NKG2D ligands link oncogenic RAS to innate immunity

Samantha S.W. Ho and Stephan Gasser
eLocation ID: e22244
http://dx.doi.org/10.4161/onci.22244
Abstract | Full Text | PDF

RAS is constitutively active in multiple types of tumor cells. We have recently demonstrated that H-RASV12 enhances the translation of ligands for the activating immune receptor NKG2D, hence rendering cells more susceptible to natural killer (NK) cell-mediated lysis. This effect depends on MAPK and PI3K signaling, but not on the DNA damage response.

Open Access Article

Metastamir-mediated immune evasion: miR-10b downregulates the stress-induced molecule MICB, hence avoid recognition by NKG2D receptor

Pinchas Tsukerman, Jonatan Enk and Ofer Mandelboim
eLocation ID: e22245
http://dx.doi.org/10.4161/onci.22245
Abstract | Full Text | PDF

Metastases are responsible for more than 90% of cancer-related deaths. We have recently reported that miR-10b inhibits the expression of MICB, a stress-induced ligand of the activating natural killer (NK)-cell receptor NKG2D. Here, we discuss our findings, which link metastasis formation to immune evasion.

Open Access Article

Single-dose cyclophosphamide synergizes with immune responses to the renal cell cancer vaccine IMA901

Steffen Walter, Toni Weinschenk, Carsten Reinhardt and Harpreet Singh-Jasuja
eLocation ID: e22246
http://dx.doi.org/10.4161/onci.22246
Abstract | Full Text | PDF

The development of efficient immunotherapies requires strong rationalization. We have recently implemented a large analysis of biomarkers in two studies involving the multi-peptide vaccine IMA901 and advanced renal cell cancer patients. Our findings demonstrate that the breadth of immune responses was associated with clinical benefits and that single-dose cyclophosphamide reduced the amount of regulatory T cells and was associated with prolonged survival after vaccination.

Open Access Article

Targeting PI3Kδ: One man’s meat is another man’s poison

Michaela Prchal-Murphy, Eva Maria Putz, Michael Freissmuth, Veronika Sexl and Eva Zebedin-Brandl
eLocation ID: e22272
http://dx.doi.org/10.4161/onci.22272
Abstract | Full Text | PDF

We have recently uncovered the indispensable role of phosphoinositide-3-kinase δ (PI3Kδ) at different stages of the canonical killing pathway of cytotoxic T lymphocytes (CTLs). The interception of PI3Kδ−conveyed signals has been considered a valuable therapeutic strategy in oncology. However, our observations predict that the benefits of this approach may be limited by a trade-off between direct anticancer effects and an impaired ability of CTLs and NK cells to attack tumor cells.

Open Access Article

NK cell-released exosomes: Natural nanobullets against tumors

Stefano Fais
eLocation ID: e22337
http://dx.doi.org/10.4161/onci.22337
Abstract | Full Text | PDF

We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool.

Open Access Article

Plasmacytoid dendritic cells deficient in IFNα production promote the amplification of FOXP3⁺ regulatory T cells and are associated with poor prognosis in breast cancer patients

Vanja Sisirak, Julien Faget, Nelly Vey, Jean-Yves Blay, Christine Ménétrier-Caux, Christophe Caux and Nathalie Bendriss-Vermare
eLocation ID: e22338
http://dx.doi.org/10.4161/onci.22338
Abstract | Full Text | PDF

The accumulation of plasmacytoid dendritic cells (pDCs) within breast carcinoma lesions is associated with a poor clinical outcome. We demonstrated that the deleterious impact of tumor-associated pDCs (TApDCs) is due to their impaired capacity to produce Type I interferon, which in turn potentiates their ability to sustain the proliferation of immunosuppressive regulatory T cells.

Open Access Article

The role of Type I interferons in immunoregulation of breast cancer metastasis to the bone

Clare Y. Slaney, Andreas Möller, Paul J. Hertzog and Belinda S. Parker
eLocation ID: e22339
http://dx.doi.org/10.4161/onci.22339
Abstract | Full Text | PDF

Breast cancer spread to distant sites is often incurable. Our recent findings demonstrate that Type I interferons secreted by tumor cells induce anti-metastatic immune responses that prevent breast cancer metastasis to the bone. This provides novel insights into the importance of the crosstalk between neoplastic and immune cells in the metastatic process.

Open Access Article

Hypoxia-driven immunosuppression contributes to the pre-metastatic niche

Jaclyn Sceneay, Belinda S. Parker, Mark J. Smyth and Andreas Möller
eLocation ID: e22355
http://dx.doi.org/10.4161/onci.22355
Abstract | Full Text | PDF

Primary tumor cells create favorable microenvironments in secondary organs, termed pre-metastatic niches, that promote the formation of metastases. Using immune competent syngenic breast cancer mouse models, we have recently demonstrated that factors secreted by hypoxic tumor cells condition pre-metastatic niches by recruiting CD11b⁺/Ly6C^med/Ly6G⁺ myeloid cells and suppressing natural killer cell functions.

Open Access Article

An anticancer therapy-elicited immunosurveillance system that eliminates tetraploid cells

Laura Senovilla, Ilio Vitale, Isabelle Martins, Oliver Kepp, Lorenzo Galluzzi, Laurence Zitvogel, Maria Castedo and Guido Kroemer
eLocation ID: e22409
http://dx.doi.org/10.4161/onci.22409
Abstract | Full Text | PDF

One of the driving forces of oncogenesis is tetraploidy, a duplication of the DNA content that, upon asymmetric cell division or progressive chromosome loss, can originate aneuploidy. Recent findings from our group indicate the existence of an immunosurveillance system that eliminates tetraploid cancer cells. We surmise that tetraploidy-inducing chemotherapeutic agents may elicit potent anticancer responses by re-activating this immunosurveillance system.

Open Access Article

Limitations for TCR gene therapy by MHC-restricted fratricide and TCR-mediated hematopoietic stem cell toxicity

Dolores J. Schendel and Bernhard Frankenberger
eLocation ID: e22410
http://dx.doi.org/10.4161/onci.22410
Abstract | Full Text | PDF

The clinical use of lymphocytes engineered to express high affinity T-cell receptors (TCRs) specific for two broadly expressed tumor-associated antigens is strongly limited by MHC-restricted fratricide of lymphocytes and TCR-mediated killing of hematopoietic stem cells. Specific clinical applications must therefore be conceived to bypass these limitations.

Open Access Article

The adenosinergic system in cancer: Key therapeutic target

Rosalinda Sorrentino, Aldo Pinto and Silvana Morello
eLocation ID: e22448
http://dx.doi.org/10.4161/onci.22448
Abstract | Full Text | PDF

High amounts of adenosine are released in the tumor mass. Depending on the levels of adenosine, as well as on the receptor subtypes that are expressed by immune cells, adenosine can affect tumor growth in different fashions. Specifically targeting CD73, the rate-limiting enzyme for the extracellular generation of adenosine, or the A3 receptor offers new therapeutic strategies to limit tumor progression.

Open Access Article

In situ conversion of tumors into autologous tumor-associated antigen vaccines by intratumoral injection of α-gal glycolipids

Uri Galili
eLocation ID: e22449
http://dx.doi.org/10.4161/onci.22449
Abstract | Full Text | PDF

The immunogenicity of autologous tumor-associated antigens (TAAs) is markedly increased upon the intratumoral injection of α-gal glycolipids, which insert into tumor cell membranes. The binding of natural anti-Gal antibodies to these glycolipids activates the complement system and recruits antigen-presenting cells (APCs), which internalize anti-Gal-coated tumor cells upon Fc/FcγR interactions. Eventually, TAA-derived peptides presented by APCs activate a T cell-mediated tumor-specific immune response.

Open Access Article

T-cell suppression mediated by regulatory T cells infiltrating hepatic tumors can be overcome by GITRL treatment

Alexander Pedroza-Gonzalez, Jaap Kwekkeboom and Dave Sprengers
eLocation ID: e22450
http://dx.doi.org/10.4161/onci.22450
Abstract | Full Text | PDF

Recently, we reported the accumulation of CD4⁺FOXP3⁺ regulatory T cells (Tregs) within the tumor mass of patients bearing liver cancer. Tumor-infiltrating Tregs (TiTregs) are active and potent suppressors of antitumor immunity. Importantly, treatment with GITRL reduced the immunosuppression mediated by TiTregs.

Open Access Article

Lymphoid neogenesis in melanoma: What does it tell us?

Nicolas van Baren, Jean-François Baurain and Pierre G. Coulie
eLocation ID: e22505
http://dx.doi.org/10.4161/onci.22505
Abstract | Full Text | PDF

Metastatic melanoma lesions sometimes host ectopic lymphoid structures exhibiting ongoing adaptive immune responses. Here, we discuss how this finding fits in our current view of antitumor immunity.

Open Access Article

The role of soluble CD40L in immunosuppression

Jeffrey Schlom, Caroline Jochems, James L. Gulley and Jianping Huang
eLocation ID: e22546
http://dx.doi.org/10.4161/onci.22546
Abstract | Full Text | PDF

We have recently performed the first comprehensive study of the potential immunosuppressive role of soluble CD40L (sCD40L). In addition, we demonstrated that serum sCD40L can potentially be used as an indicator of response to anticancer therapy, and/or to better identify those patients who would have best chances to benefit from tumor-targeting vaccines or other therapeutic modalities.

Open Access Article

Unraveling the physiological functions of exosome secretion by tumors

Angélique Bobrie and Clotilde Théry
eLocation ID: e22565
http://dx.doi.org/10.4161/onci.22565
Abstract | Full Text | PDF

To understand the physiological functions of exosomes, we have recently used the inhibition of Rab27a, which prevents exosome release but also alters other secretion pathways. Our work demonstrates that the secretion of exosomes by some tumors in vivo can influence the immune microenvironment to promote tumor progression, but also that this phenomenon cannot be generalized to all tumors and all exosomes.

Open Access Article

Cell type specific gene delivery by lentiviral vectors: New options in immunotherapy

Qi Zhou and Christian J. Buchholz
eLocation ID: e22566
http://dx.doi.org/10.4161/onci.22566
Abstract | Full Text | PDF

Many cells of the immune system are defined by distinct surface markers, which can be used to restrict gene delivery exclusively to a cell type of choice. This article explains recent findings about a CD8-specific vector that enhances the killing of tumor cells in TCR-based gene transfer strategies.

Open Access Article

Signaling via MYD88 in the pancreatic tumor microenvironment: A double-edged sword

Constantinos P. Zambirinis and George Miller
eLocation ID: e22567
http://dx.doi.org/10.4161/onci.22567
Abstract | Full Text | PDF

We have recently shown that Toll-like receptor (TLR) signaling exacerbates pancreatic fibro-inflammation and promotes carcinogenesis in mice. Paradoxically, inhibition of the TLR-MYD88 signaling pathway is pro-tumorigenic owing to the dendritic cell-mediated T_H2-polarization of CD4⁺ T cells. TLR signaling appears to be central in pancreatic cancer-associated inflammation.

Open Access Article

NKT cell adjuvants in therapeutic vaccines against hematological cancers

Stephen R. Mattarollo and Mark J. Smyth
eLocation ID: e22615
http://dx.doi.org/10.4161/onci.22615
Abstract | Full Text | PDF

Immune adjuvants aimed at initiating or re-activating host immunity against poorly immunogenic cancers represent a potential tool for immunotherapy. By employing the natural killer T (NKT) cell agonist α-galactosylceramide in a whole tumor cell therapeutic vaccine approach, we have achieved potent suppression of established hematological cancers upon the elicitation of innate and adaptive antitumor immunity.

Open Access Article

Predicting the efficacy of cancer vaccines by evaluating T-cell responses

Suzanne van Duikeren and Ramon Arens
eLocation ID: e22616
http://dx.doi.org/10.4161/onci.22616
Abstract | Full Text | PDF

In a preclinical experimental model of human papilloma virus (HPV)-induced cervical carcinoma, we have shown that the efficacy of cancer vaccines can be predicted by the evaluation of vaccine-induced T-cell responses in healthy subjects. We argue that such knowledge can be used to screen candidates for vaccination, which in turn may accelerate the development and increase the overall efficacy of cancer vaccines.

Open Access Article

Involvement of STAT3 in immune evasion during lung tumorigenesis

Hiroshi Kida, Shoichi Ihara and Atsushi Kumanogoh
eLocation ID: e22653
http://dx.doi.org/10.4161/onci.22653
Abstract | Full Text | PDF

In a recent study, we have shown that STAT3 expressed by tumor cells blunts antitumor immunity during carcinogen-induced lung tumorigenesis. STAT3 inhibits the production of pro-inflammatory chemokines and MHC Class I chain-related gene A. In contrast, STAT3 promotes the expression of MHC class I molecules. Consequently, STAT3 promotes tumor cell resistance to NK cell-mediated cytotoxicity.




CORRECTION

Open Access Article

Correction to: Foy KC, Miller MJ, Moldovan N, Carson III WE, Kaumaya PTP. Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo. OncoImmunology 2012; 1:1048–1060

Kevin C. Foy, Megan J. Miller, Nicanor Moldovan, William E. Carson and Pravin P.T. Kaumaya
eLocation ID: e23914
http://dx.doi.org/10.4161/onci.23914
Full Text | PDF