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

Célula Dendríticas y Medroxyprogesterona

Medroxyprogesterone acetate impairs human dendritic cell activation and function.

Quispe Calla NE¹, Ghonime MG², Cherpes TL², Vicetti Miguel RD¹.

¹Departments of Microbial Infection & Immunity and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA quispecalla.1@osu.edu vicettimiguel.1@osu.edu.
²Departments of Microbial Infection & Immunity and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.

 

Abstract

STUDY QUESTION:

Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?

SUMMARY ANSWER:

In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).

WHAT IS KNOWN ALREADY:

MPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.

STUDY DESIGN, SIZE, DURATION:

This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.

MAIN RESULTS AND THE ROLE OF CHANCE:

Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.

LIMITATIONS, REASON FOR CAUTION:

While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.

WIDER IMPLICATIONS OF THE FINDINGS:

Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.

STUDY FUNDING/COMPETING INTERESTS:

Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conflicts of interest to declare.
© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

KEYWORDS:

T cell proliferation; costimulatory molecule expression; dendritic cell activation; medroxyprogesterone acetate

Hum Reprod. 2015 May;30(5):1169-77. doi: 10.1093/humrep/dev035. Epub 2015 Mar 3.

http://humrep.oxfordjournals.org/content/30/5/1169.long

Md. Nirk Quispe. Past-president del GII.
Md. Rodolfo Vicetti. Ex-miembro del GII.

EGFR e Inmunoterapia

Immune biomarkers of anti-EGFR monoclonal antibody therapy.

Trivedi S¹, Concha-Benavente F², Srivastava RM¹, Jie HB¹, Gibson SP¹, Schmitt NC¹, Ferris RL³.

¹Department of Otolaryngology, University of Pittsburgh School of Medicine.
²Department of Immunology, University of Pittsburgh.
³Department of Otolaryngology, University of Pittsburgh School of Medicine Department of Immunology, University of Pittsburgh Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA ferrrl@upmc.edu.

 

Abstract

The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

KEYWORDS:

EGFR; head and neck cancer; immune biomarkers; monoclonal antibodies

Ann Oncol. 2015 Jan;26(1):40-7. doi: 10.1093/annonc/mdu156. Epub 2014 Jul 4.

http://annonc.oxfordjournals.org/content/26/1/40.long

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