TNF y Cancer

Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice.

Sobo-Vujanovic A1, Vujanovic L2, DeLeo AB3, Concha-Benavente F4, Ferris RL4, Lin Y5, Vujanovic NL6.

1. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

2. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

4. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

5. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.

6. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. vujanovicnl@upmc.edu.

Abstract

TNF is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)-injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2-Fc fusion protein (TNFR2-Fc) treatment or TNF gene deletion. In addition, gene deletion of TNFR1, which is preferentially triggered by sTNF, was temporarily blocked, whereas gene deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor cells (MDSC), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs, and indicate that sTNF could be a significant target for cancer prevention and therapy. Cancer Immunol Res; 4(5); 441-51. ©2016 AACR.

Cancer Immunol Res. 2016 May;4(5):441-51. doi: 10.1158/2326-6066.CIR-15-0104. Epub 2016 Feb 19.

http://cancerimmunolres.aacrjournals.org/content/4/5/441.long

Md. PhD. Fernando Concha. Ex-miembro del GII

Subependimoma

Subependymoma of the Cervicothoracic Spinal Cord

Yvan Maque-Acosta1 , Carol K Petito1 , Michael E Ivan2 , Charif Sidani3 and Macarena I de la Fuente4,5*

1 Departments of Pathology, University of Miami, Florida, USA
2 Department of Neurosurgery, University of Miami, Florida, USA
3 Department of Radiology, University of Miami, Florida, USA
4 Department of Neurology, University of Miami, Florida, USA
5 Sylvester Comprehensive Cancer Center, University of Miami, Florida, USA

Background

Subependymomas are rare, World Health Organization (WHO) grade I tumors [1,2]. They typically arise in the ventricles and represent less than 1% of intracranial tumors [3]. Spinal subependymomas are even less frequent, comprising approximately 2% of all symptomatic spinal cord tumors [4]. They are usually intramedullary and located in the cervical region, however thoracic and lumbar lesions have also been reported [2,5,6].

Radiologically, intracranial subependymomas present as well defined intraventricular lesions that are classically T2-weighted images (WI) hyper intense and T1WI hypo or isointense to white matter in MRI [5,7]. Heterogeneity on T2WI is often reported and is related to cystic changes, blood products or calcifications, particularly in larger lesions [5]. Calcifications and blood products can manifest as low signal intensity on T2WI gradient echo sequence. Subependymomas typically do not enhance or only mildly enhance. Avid enhancement has been reported particularly in lesions located in the fourth ventricle. The tumor size typically ranges from 1 to 2 cm, however lesions greater than 5 cm have also been reported [2,5]. Spinal subependymomas usually present as eccentric, well-defined lesions with mild to moderate enhancement. Lesions of the spine have significant associated edema [2,6].

Histologically, subependymomas are characterized by the presence of nuclear clustering and a densely fibrillar and paucicellular background [1]. Microcysts can be present, particularly in lesions located closer to the foramen of Monro. Subtle pseudorosettes can also be seen [1,8]. In tumors located far from the foramen of Monro, the nuclear clustering is more prominent. Occasionally, an ependymoma component can be identified, although this is more common in fourth ventricle tumors. By immunohistochemistry, subependymoma are diffusely positive for glial fibrillary acidic protein (GFAP) which demonstrate its glial origin and positive for epithelial membrane antigen (EMA) (showing a dot-like pattern) which is consistent with an ependymal origin. They usually have a low Ki-67 proliferative index, although it can be variable [1,8].

We describe a case of spinal subependymoma and discuss the clinical, radiographic and histological characteristics.

Citation: Maque-Acosta Y, Petito CK, Ivan ME, Sidani C, de la Fuente MI (2016) Subependymoma of the Cervicothoracic Spinal Cord. J Neurol Neurobiol 2(3): doi http://dx.doi.org/10.16966/2379-7150.123

Avaliable: https://www.sciforschenonline.org/journals/neurology/JNNB-2-123.php

Md. Yvan Maque-Acosta, Ex-Miembro GII

HPV y CD8

Enhanced Cytotoxic CD8 T Cell Priming Using Dendritic Cell-Expressing Human Papillomavirus-16 E6/E7-p16INK4 Fusion Protein with Sequenced Anti-Programmed Death-1.

Garcia-Bates TM1, Kim E2, Concha-Benavente F3, Trivedi S4, Mailliard RB5, Gambotto A2, Ferris RL6.

1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15232;

2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15232;

3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15232; and.

4. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232;

5. Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15232;

6. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15232; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15232; and Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 ferrisrl@upmc.edu.

Abstract

The incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma has increased in recent decades, though HPV prevention vaccines may reduce this rise in the future. HPV-related cancers express the viral oncoproteins E6 and E7. The latter inactivates the tumor suppressor protein retinoblastoma (Rb), which leads to the overexpression of p16(INK4) protein, providing unique Ags for therapeutic HPV-specific cancer vaccination. We developed potential adenoviral vaccines that express a fusion protein of HPV-16 E6 and E7 (Ad.E6E7) alone or fused with p16 (Ad.E6E7p16) and also encoding an anti-programmed death (PD)-1 Ab. Human monocyte-derived dendritic cells (DC) transduced with Ad.E6E7 or Ad.E6E7p16 with or without Ad.αPD1 were used to activate autologous CD8 CTL in vitro. CTL responses were tested against naturally HPV-infected head and neck squamous cell carcinoma cells using IFN-γ ELISPOT and [(51)Cr]release assay. Surprisingly, stimulation and antitumor activity of CTL were increased after incubation with Ad.E6E7p16-transduced DC (DC.E6E7p16) compared with Ad.E6E7 (DC.E6E7), a result that may be due to an effect of p16 on cyclin-dependent kinase 4 levels and IL-12 secretion by DC. Moreover, the beneficial effect was most prominent when anti-PD-1 was introduced during the second round of stimulation (after initial priming). These data suggest that careful sequencing of Ad.E6E7.p16 with Ad.αPD1 could improve antitumor immunity against HPV-related tumors and that p16 may enhance the immunogenicity of DC, through cyclin-dependent pathways, Th1 cytokine secretion, and by adding a nonviral Ag highly overexpressed in HPV-induced cancers.

J Immunol. 2016 Mar 15;196(6):2870-8. doi: 10.4049/jimmunol.1502027. Epub 2016 Feb 5.

http://www.jimmunol.org/content/196/6/2870.long

Md. PhD. Fernando Concha. Ex-miembro del GII

EGFR y Cancer de Cabeza y Cuello

Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer.

Concha-Benavente F1, Srivastava RM2, Trivedi S2, Lei Y3, Chandran U4, Seethala RR5, Freeman GJ6, Ferris RL7.

1. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

2. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. Department of Periodontics and Oral Medicine, School of Dentistry and Department of Otolaryngology-Head and Neck Surgery, School of Medicine. University of Michigan, Ann Arbor, Michigan.

4. Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.

5. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

6. Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.

7. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.

Abstract

Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.

Cancer Res. 2016 Mar 1;76(5):1031-43. doi: 10.1158/0008-5472.CAN-15-2001. Epub 2015 Dec 16.

http://cancerres.aacrjournals.org/content/76/5/1031.long

Md. PhD. Fernando Concha. Ex-miembro del GII

EGFR y Cáncer de Cabeza y Cuello

STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.

Srivastava RM¹, Trivedi S¹, Concha-Benavente F², Hyun-Bae J¹, Wang L¹, Seethala RR³, Branstetter BF 4th⁴, Ferrone S⁵, Ferris RL⁶.

¹Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
²Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
³Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁴Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁵Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
⁶Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.

 

Abstract

The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies, and chromatin immunoprecipitation (ChIP) assays were performed using HNC cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. A prospective phase II clinical trial of neoadjuvant cetuximab was used to correlate HLA class I expression with clinical response in HNC patients. EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology-containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression, augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which was abrogated in STAT1^-/- cells. Cetuximab enhanced HNC cell recognition by EGFR_853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3_271-279). HLA class I upregulation was significantly associated with clinical response in cetuximab-treated HNC patients. EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I downregulation was more prominent in clinical responders to cetuximab therapy, supporting an important role for adaptive immunity in cetuximab antitumor activity. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity. Cancer Immunol Res; 3(8); 1-10. ©2015 AACR.

©2015 American Association for Cancer Research.

Cancer Immunol Res. 2015 May 13. [Epub ahead of print]

http://cancerimmunolres.aacrjournals.org/content/early/2015/07/08/2326-6066.CIR-15-0053.abstract?sid=417db2a5-a149-461c-a080-8c3722e523a3

Md. PhD. Fernando Concha. Ex-miembro del GII

HSV-2 y Vaginosis Bacterial

Risk of Bacterial Vaginosis Among Women With Herpes Simplex Virus Type 2 Infection: A Systematic Review and Meta-analysis.

Esber A¹, Vicetti Miguel RD², Cherpes TL², Klebanoff MA³, Gallo MF¹, Turner AN⁴.

¹Division of Epidemiology.
²Department of Microbial Infection and Immunity Department of Obstetrics and Gynecology.
³Department of Pediatrics Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
⁴Division of Infectious Diseases, Department of Internal Medicine, Ohio State University.

 

Abstract

BACKGROUND:

Bacterial vaginosis (BV) is a perturbation of vaginal flora characterized by reduced levels of lactobacilli and concomitant overgrowth of anaerobic bacterial species. BV is highly prevalent and associated with multiple adverse outcomes, including enhanced human immunodeficiency virus transmission. Because recent reports reveal that herpes simplex virus type 2 (HSV-2) infection may increase BV risk, we initiated a systematic review and meta-analysis of the link between HSV-2 infection and BV.

METHODS:

We searched the MEDLINE, EMBASE, and CENTRAL databases to identify articles posted before 1 December 2014. Two screeners independently reviewed the titles and abstracts of all identified articles, reviewed the full text of articles deemed potentially eligible, and extracted data from 14 cross-sectional and 3 prospective studies. Using random-effects models, we computed separate pooled estimates for cross-sectional and prospective studies.

RESULTS:

The pooled odds ratio for cross-sectional studies was 1.60 (95% confidence interval, 1.32-1.94). Stronger support for the causal effect of HSV-2 infection on BV risk was revealed by the summary relative risk for the prospective studies, which was 1.55 (95% confidence interval, 1.30-1.84), with minimal heterogeneity (I² = 0).

CONCLUSIONS:

These analyses imply that HSV-2 infection is an important BV risk factor. Pharmacologic HSV-2 suppression may reduce BV incidence and BV-associated adverse events.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

KEYWORDS:

bacterial vaginosis; herpes simplex virus type 2; meta-analysis; systematic review

J Infect Dis. 2015 Jul 1;212(1):8-17. Epub 2015 Jan 14.

http://jid.oxfordjournals.org/content/212/1/8.long

Md. Rodolfo Vicetti. Ex-miembro del GII.

HSV-2

Use of transcriptional profiling to delineate the initial response of mice to intravaginal herpes simplex virus type 2 infection.

Cherpes TL¹, Harvey SA, Phillips JM, Vicetti Miguel RD, Melan MA, Quispe Calla NE, Hendricks RL.

¹Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA. cherpest@pitt.edu

 

Abstract

Intravaginal (ivag) infection of mice with herpes simplex virus type 2 (HSV-2) causes genital tissue damage, quickly followed by development of fatal encephalopathy. To delineate initial host responses generated by HSV-2 infection, here oligonucleotide microarrays compared gene expression in vaginal tissue from uninfected mice and mice 1, 2, 3, 4, 5, 6, or 7 days after ivag infection with 10(4) pfu HSV-2. While comparison of mRNA expression in uninfected and HSV-infected vaginal tissue detected few changes during the first 2 days post infection (dpi), there were 156 genes whose expression was first significantly altered 3 dpi that remained significantly modified at all later time points examined. These 156 genes were significantly enriched in canonical pathways associated with interferon (IFN) signaling, activation of IFN elements by intracellular pattern recognition receptors, and antiviral immunity induced by cytosolic RIG-like receptors. Evaluation of this gene set with the National Center for Biotechnology Information Gene and INTERFEROME databases corroborated pathway analysis, as function of most (53%) were linked to IFN-mediated host immunity. In the final set of experiments, ivag administration of the Toll-like receptor 3 agonist polyinosinic: polycytidylic acid (poly I:C) 24 h before ivag HSV-2 infection reduced the incidence of genital pathology and encephalopathy, while these poly I:C-treated mice were subsequently protected from ocular HSV-2 challenge lethal to uninfected controls. The latter results imply that the exuberant antiviral immunity produced in our experimental model is simply formed too late to prevent viral replication and dissemination, and that poly I:C-induced formation of an antiviral state protecting against primary ivag infection also permits development of HSV-specific protective immunity.

Viral Immunol. 2013 Jun;26(3):172-9. doi: 10.1089/vim.2012.0093. Epub 2013 May 2.

 http://online.liebertpub.com/doi/abs/10.1089/vim.2012.0093

Md. Rodolfo Vicetti. Ex-miembro del GII.

Cáncer y Citocinas

Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents.

 

Valdivia-Silva J1,2, Medina-Tamayo J1,2, Garcia-Zepeda EA3,4.

¹Chemokine Biology Research Laboratory, Programa Institucional de Investigación en Cancer de Mama, Mexico DF 04510, Mexico.
²Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico DF 04510, Mexico.
³Chemokine Biology Research Laboratory, Programa Institucional de Investigación en Cancer de Mama, Mexico DF 04510, Mexico. garciaze@unam.mx.
⁴Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico DF 04510, Mexico. garciaze@unam.mx.

 

Abstract

Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/ chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP) with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer.

KEYWORDS:

cancer; chemokine; chemokine receptors; cytokines; inflammation; microbial infections; peptides

Int J Mol Sci. 2015 Jun 8;16(6):12958-12985.

http://www.mdpi.com/1422-0067/16/6/12958

Md PhD Julio Valdivia Silva. Fundador del GII