<i>In vivo</i> Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Ugel, Stefano; Zoso, Alessia; Santo, Carmela De; Yu, Li; Marigo, Ilaria; Zanovello, Paola; Scarselli, Elisa; Cipriani, Barbara; Oelke, Mathias; Schneck, Jonathan P.; Bronte, Vincenzo

doi:10.1158/0008-5472.can-09-0400

Cited by 62 publications

(50 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, significant fractions of IFN-g-competent CD8 þ T CM cells were found in slightly longer ex vivo assays (24 hours). Interestingly, the 24-hour ICP assay also allowed enumeration of intermediate/low avidity TRP-2-specific memory CD8 þ T cells (31). We believe .…”

Section: Discussionmentioning

confidence: 88%

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

et al. 2013

View full text Add to dashboard Cite

Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumorspecific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-g-competent memory CD8þ T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease. Cancer Res; 73(12); 3545-54. Ó2013 AACR.

show abstract

Section: Discussionmentioning

confidence: 88%

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

et al. 2013

View full text Add to dashboard Cite

show abstract

“…That said, there may be circumstances wherein lower avidity cells play a critical role. For example, cells exhibiting reduced avidity may be protected from exhaustion in models of chronic antigen exposure (15) and may play important roles in the clearance of some tumor cells (54,57,58).…”

mentioning

confidence: 99%

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

et al. 2013

View full text Add to dashboard Cite

Numerous studies have demonstrated a critical role for T cell avidity in predicting in vivo efficacy. Even though the measurement of avidity is now a routine assessment for the analysis of effector and memory T cell populations, our understanding of how this property is controlled in vivo at both the population and individual cell levels is limited. Our previous studies have identified high avidity as a property of the initial effector population generated in mice following respiratory virus infection. As the response progresses, lower avidity cells appear in the effector pool. The studies described here investigate the mechanistic basis of this in vivo regulation of avidity. We present data supporting in vivo avidity modulation within the early high avidity responders that results in a population of lower avidity effector cells. Changes in avidity were correlated with decreased lck expression and increased sensitivity to lck inhibitors in effector cells present at late versus early times postinfection. The possibility of tuning within select individual effectors is a previously unappreciated mechanism for the control of avidity in vivo.

show abstract

“…It has also been reported that i.v. injection of Kb-expressing aAPC into C57BL/6 mice resulted in decreased lung metastasis of tumor 21 . Importantly, these data demonstrate that aAPC traffic to the lung and are able to activate effector T cell subsets.…”

Section: Discussionmentioning

confidence: 96%

Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells

East

Sun

Webb

2012

JoVE

View full text Add to dashboard Cite

Abstract. NKT cells express an invariant TCRα chain rearrangement: Vα14Jα18 in mice and Vα24Jα18 in humans, which is associated with Vβ chains of limited diversity [3][4][5][6] , and are referred to as canonical or invariant NKT (iNKT) cells. Similar to conventional T cells, NKT cells develop from CD4-CD8-thymic precursor T cells following the appropriate signaling by CD1d 7. The potential to utilize NKT cells for therapeutic purposes has significantly increased with the ability to stimulate and expand human NKT cells with α-Galactosylceramide (α-GalCer) and a variety of cytokines 8 . Importantly, these cells retained their original phenotype, secreted cytokines, and displayed cytotoxic function against tumor cell lines. Thus, ex vivo expanded NKT cells remain functional and can be used for adoptive immunotherapy. However, NKT cell based-immunotherapy has been limited by the use of autologous antigen presenting cells and the quantity and quality of these stimulator cells can vary substantially. Monocyte-derived DC from cancer patients have been reported to express reduced levels of costimulatory molecules and produce less inflammatory cytokines 9,10 . In fact, murine DC rather than autologous APC have been used to test the function of NKT cells from CML patients 11 . However, this system can only be used for in vitro testing since NKT cells cannot be expanded by murine DC and then used for adoptive immunotherapy. Thus, a standardized system that relies on artificial Antigen Presenting Cells (aAPC) could produce the stimulating effects of DC without the pitfalls of allo-or xenogeneic cells 12,13 . Herein, we describe a method for generating CD1d-based aAPC. Since the engagement of the T cell receptor (TCR) by CD1d-antigen complexes is a fundamental requirement of NKT cell activation, antigen: CD1d-Ig complexes provide a reliable method to isolate, activate, and expand effector NKT cell populations. Video LinkThe video component of this article can be found at https://www.jove.com/video/4333/ Protocol 1. Generation of aAPC ); Bead Wash Buffer (1X PBS+5% Human AB serum + 0.02% sodium azide); Complete medium (RPMI medium +100 mM sodium pyruvate,10 mM non-essential vitamin solution, 100 mM MEM Vitamin solution, 1% 2-mercaptoethanol, 10 μM ciprofloxacin, 5% Human AB serum); MACS buffer (1 L PBS free of Ca 2+ and Mg 2+, 5 g BSA, and 2 mmol EDTA). 2. Rinse 1 ml Dynabeads M-450 Epoxy beads with 3 ml sterile 0.1 M Borate buffer (boric acid and water, pH 7.0-7.4) in a 5 ml clear borosilicate glass threaded vial. 3. In a separate 1.5 ml microcentrifuge tube, add 100 μg hCD1d-Ig dimer and 20 μg costimulatory molecules (example: anti-CD28mAb) to 1 ml PBS w/o Ca 2+ or Mg 2+ . 4. Place bead containing glass vial on magnet and aspirate borate buffer from beads. Add protein mixture from step 1.2 to glass vial and replace cap. Mix immediately by inverting the vial, cover the cap with parafilm, and place on a rotator and incubate overnight at 4 °C. 5. The next day, place glass vial on magnet and remove protein mixture, while carefu...

show abstract

In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Cited by 62 publications

References 28 publications

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells

Contact Info

Product

Resources

About

In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Cited by 62 publications

References 28 publications

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

In vivoModulation of Avidity in Highly Sensitive CD8+Effector T Cells Following Viral Infection

Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells

Contact Info

Product

Resources

About

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection