Peptide-loaded langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo Journal Article


Authors: Romano, E.; Rossi, M.; Ratzinger, G.; De Cos, M. A.; Chung, D. J.; Panageas, K. S.; Wolchok, J. D.; Houghton, A. N.; Chapman, P. B.; Heller, G.; Yuan, J.; Young, J. W.
Article Title: Peptide-loaded langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo
Abstract: Purpose: We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity. Experimental Design: American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. Results: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen-specific effector memory T cells (TEMRA) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. Conclusions: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. ©2011 AACR.
Journal Title: Clinical Cancer Research
Volume: 17
Issue: 7
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2011-04-01
Start Page: 1984
End Page: 1997
Language: English
DOI: 10.1158/1078-0432.ccr-10-3421
PROVIDER: scopus
PUBMED: 21355077
PMCID: PMC3743659
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Marco Rossi
    9 Rossi
  2. Glenn Heller
    291 Heller
  3. Jedd D Wolchok
    656 Wolchok
  4. Maria De Los Angeles De Cos
    3 De Cos
  5. Paul Chapman
    246 Chapman
  6. Katherine S Panageas
    327 Panageas
  7. James W Young
    250 Young
  8. Emanuela Romano
    11 Romano
  9. Jianda Yuan
    100 Yuan
  10. Alan N Houghton
    266 Houghton
  11. David Chung
    78 Chung