lunes, 27 de julio de 2015

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 EGFR853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271-279). 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

jueves, 2 de julio de 2015

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.