Stem Cells y Cancer

Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid tumors.

Amara I1, Pramil E1, Senamaud-Beaufort C1, Devillers A1, Macedo R2, Lescaille G2, Seguin J3, Tartour E4, Lemoine FM2, Beaune P1, de Waziers I5.

1. INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.

2. Sorbonne University, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France.

3. INSERM U1022, CNRS UMR8151, Paris Descartes University, Faculty of Pharmacy, Chimie ParisTech, Sorbonne Paris Cité, Chemical, Genetic and Imaging Pharmacology Laboratory, 4 avenue de l'observatoire, 75006 Paris, France.

4. INSERM U970, PARCC, Paris Descartes University, Sorbonne Paris Cité. Faculté de Médecine, 20 rue Leblanc, 75015 Paris, France.

5. INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France. Electronic address: isabelle.waziers@parisdescartes.fr.

Abstract

Gene-directed enzyme pro-drug therapy (GDEPT) consists of expressing, in tumor cells, a suicide gene which converts a pro-drug into cytotoxic metabolites, in situ. In a previous work, we demonstrated that the combination of the suicide gene CYP2B6TM-RED (a fusion of a triple mutant of CYP2B6 with NADPH cytochrome P450 reductase) and cyclophosphamide (CPA) constituted a powerful treatment for solid tumors. In this work, we investigated the use of mesenchymal stem cells (MSCs) as cellular vehicles for the delivery of our suicide gene. MSCs were genetically engineered ex-vivo to stably express CYP2B6TM-RED. Ex vivo and in vivo investigations showed that MSCs expressing CYP2B6TM-RED were able 1) to bioactivate CPA and produce local cytotoxic metabolites in tumor sites and 2) to destroy neighboring tumor cells through a bystander effect. Intratumoral injections of CYP2B6TM-RED-MSCs and CPA completely eradicated tumors in 33% of mice without recurrence after 6months. Rechallenge experiments demonstrated an efficient immune response. These data suggest that MSCs expressing CYP2B6TM-RED with CPA could represent a promising treatment for solid tumors to test in future clinical trials.

J Control Release. 2016 Oct 10;239:82-91. doi: 10.1016/j.jconrel.2016.08.019. Epub 2016 Aug 23.

http://www.sciencedirect.com/science/article/pii/S016836591630548X

Md. PhD. Rodney Macedo. Past-president del GII.

Chlamydia trachomatis e infertilidad

Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage

Rodolfo D. Vicetti Miguel1 , Nirk E. Quispe Calla1 , Stephen D. Pavelko1 , Thomas L. Cherpes1,2

1. Department of Microbial infection & Immunity, The Ohio State University College of Medicine, Columbus, Ohio, United States of America 
2. Department of Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, Ohio, United States of America 

Abstract

While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response.

Citation: Vicetti Miguel RD, Quispe Calla NE, Pavelko SD, Cherpes TL. Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage. Kanellopoulos-Langevin C, ed. PLoS ONE. 2016;11(9):e0162445. doi:10.1371/journal.pone.0162445.

Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015975/

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

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

HLA-I and Cancer

Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells.

Concha-Benavente F1, Srivastava R2, Ferrone S3, Ferris RL4.

1. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

2. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.

3. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

4. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. Electronic address: ferrisrl@upmc.edu.

Abstract

Experimental as well as clinical studies demonstrate that the immune system plays a major role in controlling generation and progression of tumors. The cancer immunoediting theory supports the notion that tumor cell immunogenicity is dynamically shaped by the immune system, as it eliminates immunogenic tumor cells in the early stage of the disease and then edits their antigenicity. The end result is the generation of a tumor cell population able to escape from immune recognition and elimination by tumor infiltrating lymphocytes. Two major mechanisms, which affect the target cells and the effector phase of the immune response, play a crucial role in the editing process. One is represented by the downregulation of tumor antigen (TA) processing and presentation because of abnormalities in the HLA class I antigen processing machinery (APM). The other one is represented by the anergy of effector immune infiltrates in the tumor microenvironment caused by aberrant inhibitory signals triggered by immune checkpoint receptor (ICR) ligands, such as programmed death ligand-1 (PD-L1). In this review, we will focus on tumor immune escape mechanisms caused by defects in HLA class I APM component expression and/or function in different types of cancer, with emphasis on head and neck cancer (HNC). We will also discuss the immunological implications and clinical relevance of these HLA class I APM abnormalities. Finally, we will describe strategies to counteract defective TA presentation with the expectation that they will enhance tumor recognition and elimination by tumor infiltrating effector T cells.

Oral Oncol. 2016 Jul;58:52-8. doi: 10.1016/j.oraloncology.2016.05.008. Epub 2016 Jun 2.

http://www.sciencedirect.com/science/article/pii/S1368837516300549

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

Vacunas HPV y Cancer de Cabeza y Cuello

Intra-cheek immunization as a novel vaccination route for therapeutic vaccines of head and neck squamous cell carcinomas using plasmo virus-like particles.

Macedo R1, Rochefort J2, Guillot-Delost M1, Tanaka K1, Le Moignic A1, Noizat C1, Baillou C1, Mateo V1, Carpentier AF3, Tartour E4, Bertolus C5, Bellier B6, Lescaille G2, Lemoine FM7.

1. Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Center d'Immunologie et Maladies Infectieuses (CIMI-Paris) , Paris, France.

2. Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Center d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France; Paris Diderot/Paris 07, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe hospitalier Pitié-Salpêtrière, Department of Odontology, Paris, France.

3. Université Paris 13, AP-HP, Hôpital Avicenne, Department of Neurology, Bobigny, France.

4. Paris Descartes/Paris 05, Sorbonne Paris Cité, INSERM U970, Paris-Cardiovascular Research Center (PARC), AP-HP, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique , Paris, France.

5. Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Center d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France; Sorbonne Universités, UPMC Univ-Paris 06, AP-HP, Groupe hospitalier Pitié-Salpêtrière, Department of Maxillofacial Surgery, Paris, France.

6. Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U959, CNRS, FRE 3632, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.

7. Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Center d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Biotherapies, Paris, France.

Abstract

Despite current therapy, head and neck squamous cell carcinomas (HNSCCs) arising from various mucosal sites of the upper aero-digestive tract frequently relapse in a loco-regional manner and have a poor prognosis. Our objective was to validate an innovative mucosal route of vaccination using plasmo virus-like particles (pVLPs) in a pre-clinical orthotopic model of HNSCCs. For this purpose, we used pVLP-E7, that are plasmid DNA encoding retroviral virus-like particles carrying a truncated E7 oncoprotein from HPV-16 as antigen model, to vaccinate mice bearing pre-established TC-1 tumors implanted into the buccal mucosa. pVLP-E7 were combined with clinical grade TLR agonists (Imiquimod and CpG-ODN). In this pre-clinical orthotopic model, whose tumor microenvironment resembles to those of human HNSCCs, different mucosal vaccination routes were tested for their ability to elicit efficient immune and antitumoral responses. Results showed that mucosal intra-cheek (IC) vaccinations using pVLP-E7, comparatively to intradermic vaccinations (ID), gave rise to higher mobilization of mucosal (CD49a(+)) CD8(+) specific effector T cells in both tumor draining lymph nodes (TdLNs) and tumor microenvironment resulting in better antitumor effects and in a long-term protection against tumor rechallenge. In vivo CD8(+) depletion demonstrated that antitumoral effects were fully dependent upon the presence of CD8(+) T cells. Validation of IC mucosal vaccinations with pVLPs combined with adjuvants using a pre-clinical orthotopic model of HNSCC provides valuable pre-clinical data to rapidly envision the use of such therapeutic vaccines in patients with HNSCCs, inasmuch as vaccinal components and adjuvants can be easily obtained as clinical grade reagents.

Oncoimmunology. 2016 Jul 6;5(7):e1164363. doi: 10.1080/2162402X.2016.1164363. eCollection 2016.

http://www.tandfonline.com/doi/abs/10.1080/2162402X.2016.1164363?journalCode=koni20

Md. PhD. Rodney Macedo. Past-president del GII.