CD137 y Cancer de Cabeza y Cuello

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer

Srivastava RM1, Trivedi S1, Concha-Benavente F2, Gibson SP1, Reeder C1, Ferrone S3, Ferris RL4,2,5.

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

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

3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

4. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.

5. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Abstract

PURPOSE:

Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.

EXPERIMENTAL DESIGN:

CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells.

RESULTS:

CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab.

CONCLUSIONS:

These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR.

Clin Cancer Res. 2017 Feb 1;23(3):707-716. doi: 10.1158/1078-0432.CCR-16-0879. Epub 2016 Aug 5.

http://clincancerres.aacrjournals.org/content/23/3/707.long

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

Chlamydia trachomatis y levonorgestrel

Dendritic cell function and pathogen-specific T cell immunity are inhibited in mice administered levonorgestrel prior to intranasal Chlamydia trachomatis infection

Nirk E. Quispe Calla, Rodolfo D. Vicetti Miguel, Ao Mei, Shumin Fan, Jocelyn R. Gilmore & Thomas L. Cherpes

1. Department of Microbial infection &Immunity, The Ohio State University College of Medicine, Columbus, OH, 43210, USA.

2. Department of Obstetrics &Gynecology The Ohio State University College of Medicine, Columbus, OH, 43210, USA.

The growing popularity of levonorgestrel (LNG)-releasing intra-uterine systems for long-acting reversible contraception provides strong impetus to define immunomodulatory properties of this exogenous progestin. In initial in vitro studies herein, we found LNG significantly impaired activation of human dendritic cell (DCs) and their capacity to promote allogeneic T cell proliferation. In follow-up studies in a murine model of intranasal Chlamydia trachomatis infection, we analogously found that LNG treatment prior to infection dramatically reduced CD40 expression in DCs isolated from draining lymph nodes at 2 days post infection (dpi). At 12 dpi, we also detected significantly fewer CD4⁺ and CD8⁺ T cells in the lungs of LNG-treated mice. This inhibition of DC activation and T cell expansion in LNG-treated mice also delayed chlamydial clearance and the resolution of pulmonary inflammation. Conversely, administering agonist anti-CD40 monoclonal antibody to LNG-treated mice at 1 dpi restored lung T cell numbers and chlamydial burden at 12 dpi to levels seen in infected controls. Together, these studies reveal that LNG suppresses DC activation and function, and inhibits formation of pathogen-specific T cell immunity. They also highlight the need for studies that define in vivo effects of LNG use on human host response to microbial pathogens. 

Scientific Reports. 2016 Nov 28;6:37723. doi: 10.1038/srep37723.

https://www.nature.com/articles/srep37723

Md. Rodolfo D. Vicetti Miguel, Ex-Miembro del GII

Md. Nirk E. Quispe Calla, Past President del GII

Herpes Simplex Virus type2 and contraception

Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection

N E Quispe Calla1, R D Vicetti Miguel1, P N Boyaka2, L Hall-Stoodley1, B Kaur3, W Trout4, S D Pavelko1 and T L Cherpes1,4

1. Department of Microbial Infection and Immunity, Columbus, Ohio, USA

2. Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA

3. Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio, USA

4.Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio, USA

Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). Although observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, we herein found that DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed that DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed that inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

Mucosal Immunology (2016) 9, 1571–1583; doi:10.1038/mi.2016.22

https://www.nature.com/mi/journal/v9/n6/full/mi201622a.html

Md. Rodolfo D. Vicetti Miguel, Ex-Miembro del GII

Md. Nirk E. Quispe Calla, Past President del GII