March 2014 Edition
 |
Very Small Size Proteoliposomes Abrogate Cross-Presentation of Tumor Antigens by Myeloid-Derived Suppressor Cells and Induce their Differentiation to Dendritic Cells |
| Fernández A, Oliver L, Alvarez R, Hernández A, Raymond J, Fernández LE and Mesa C Journal for ImmunoTherapy of Cancer 2014, 2:5 (11 March 2014) |
Background:
Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. Very Small Size Proteoliposomes (VSSP) is used as adjuvant by four therapeutic cancer vaccines currently in phase I and II clinical trials. We previously found that VSSP reduces the suppressive function of MDSCs, then activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. However the mechanistic explanation for the immunomodulatory effect of this adjuvant in TB hosts has not been addressed before.
Methods:
TB mice were inoculated with VSSP and MDSCs isolated and characterized by their expression of Arg1 and Nos2 genes by RT-PCR. The effect of VSSP on antigen crosspresentation by MDSCs, regulatory T cells (Tregs) expansion and MDSCs differentiation towards dendritic cells (DCs) was analyzed by FACS. Student’s t test or ANOVA and Tukey’s tests were used for statistical analyses.
Results:
After inoculating VSSP into TB mice, a significant reduction of Arg1 and Nos2 gene expression was observed in recovered MDSCs. Concurrently the ability of these cells to induce down-regulation of CD3ζ chain on T cells was lost. Likewise in mice inoculated with the adjuvant lower percentages of Tregs were detected. In vitro, VSSP treatment was enough to differentiate MDSCs into phenotypically mature DCs, eliminating the former suppressive effect. Noteworthy, in vivo administration of VSSP to OVA-expressing (EG.7) TB mice abrogated this model antigen cross-presentation by splenic MDSCs. Similar results were obtained even when OVA antigen was administered into these TB mice formulated in VSSP. On the contrary, immunization with the same protein in polyI:C did not change the percentage of MDSCs expressing SIINFEKL/H-2Kb complexes, whereas a concomitant injection of VSSP aborted the limitations of polyI:C in this setting.
Conclusions:
Altogether, these results indicate that VSSP has the peculiar capacity of inhibiting TAA cross-presentation and certain suppressive mechanisms on MDSCs which in turn, combined with the ability to induce differentiation of these cells into antigen-presenting cells (APCs), sustains this adjuvant as an ideal immunomodulator for cancer immunotherapy.
"The manuscript describes the differentiation of tumor-induced MDSCs towards mature DCs and the inhibition of certain suppressive mechanisms associated to MDSCs due to the treatment with Very Small Size Proteoliposomes (VSSP), an adjuvant currently used by therapeutic cancer vaccines in the clinics. Remarkably, VSSP abrogates cross-presentation of tumor antigens by splenic MDSCs, which is required to induce tolerance of tumor-specific CTLs,” noted corresponding author on the paper, Audry Fernández, MSc. She continued that “these results suggest that VSSP could be able to overcome tumor-induced immunosuppression and thus it represents a suitable immunomodulator for cancer immunotherapy.”
To continue reading, please click HERE.
|
Stem cells and cancer immunotherapy: Arrowhead's 2nd annual cancer immunotherapy conference |
| Bot A, Chiriva-Internati M, Cornforth A, Czerniecki BJ, Ferrone S, Geles K, Greenberg PD, Hurt E et al. Journal for ImmunoTherapy of Cancer 2014, 2:6 (20 March 2014) |
Abstract:
Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.
"Immunotherapy is emerging as a major therapeutic modality for cancer patients. While platform technologies become increasingly more potent, a major limiting factor is represented by the difficulty to define new targets that afford a safe and durable clinical response," said corresponding author on the paper Adrian Bot, MD, PhD. "This conference brought together leading investigators from academia and industry, with interest in targeting the cancerous process at its very core, represented by cells endowed with stem cell-like properties and resilient to conventional therapies."
To continue reading, please click HERE.
Highly Accessed Article Update
Mechanism of Tumor Rejection with Doublets of CTLA-4, PD-1/PD-L1, or IDO Blockade Involves Restored IL-2 Production and Proliferation of CD8+ T Cells Directly Eithin the Tumor Microenvironment
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R and Gajewski TF Journal for ImmunoTherapy of Cancer 2014, 2:3 (18 February 2014)
Waived Article Processing Charges for SITC Members
SITC members – Don’t forget to take advantage of waived article processing charges when you submit your research to JITC (a $2,400 USD savings).
Need to renew your membership dues for 2014 or become a SITC Member to take advantage of this benefit? Simply click here.
Members and non-members alike are invited to submit their manuscript in the following categories:
- Basic Tumor Immunology: including tumor antigens, innate and adaptive anti-tumor immune mechanisms, immune regulation, immune response, cancer and inflammation, preclinical models, chemotherapy and radiotherapy interactions with the anti-tumor immune response, oncolytic viruses
Section Editor: Cornelis J.M. Melief, MD, PhD - ISA Therapeutics BV
- Case Reports: reporting unusual or unexpected clinical cases that expand the field of general medical knowledge
Section Editor: F. Stephen Hodi, Jr., MD - Dana-Farber Cancer Institute
- Clinical/Translational Cancer Immunotherapy: including first in man clinical trials, phase II/III clinical studies, immune monitoring investigations, tumor microenvironment, host genetics and clinical outcome, updates on clinical trials
Section Editor: F. Stephen Hodi, Jr., MD - Dana-Farber Cancer Institute
- Immunotherapy Biomarkers: including predictive/prognostic biomarker studies, gene expression studies in cancer immunotherapy, serological immune biomarkers, multiparameter flow cytometry-defined immune biomarkers, high content immunohistological studies
Section Editor: Lisa H. Butterfield, PhD - University of Pittsburgh Cancer Institute
- Reviews/Editorials: triggering discussion on hot topics and innovative concepts
Section Editors:
Bernard A. Fox, PhD - Earle A. Chiles Research Institute
Thomas F. Gajewski, MD, PhD - University of Chicago
JITC Editor-in-Chief
Pedro J. Romero, MD - Ludwig Center for Cancer Research
To submit your research visit: www.sitcancer.org/journal
