Intralymphatic dendritic cell vaccination induces tumor antigen - specific, skin-homing T lymphocytes

Amelia Grover, Grace J. Kim, Gregory Lizée, Mary Tschoi, Gang Wang, John R. Wunderlich, Steven A. Rosenberg, Samuel T Hwang, Patrick Hwu

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Purpose: The identification of tumor antigens recognized by cytotoxic and T helper lymphocytes has led to the development of specific cancer vaccines. Immunization with tumor antigen-pulsed dendritic cells has proved effective at eliciting elevated levels of tumor antigen - specific T cells in patient blood, but objective clinical responses remain rare, suggesting that vaccine-induced T cells are not trafficking optimally to site(s) of tumor burden. Accumulating evidence from animal models suggests that route of immunization can have a substantial influence on the subsequent migration of primed, activated T cells in vivo. Experimental Design: In a clinical trial designed to elicit more effective cytotoxic T-cell mediated antitumor responses, metastatic melanoma patients were immunized directly via a peripheral intralymphatic route with autologous dendritic cells pulsed with HLA-A*0201-restricted melanoma-associated peptide antigens derived from MART-1 and gp100. Results: Within 10 days of intralymphatic dendritic cell vaccination, four of six patients developed dramatic and diffuse erythematous rashes in sun-exposed areas of skin that showed extensive T-cell infiltration. CTLs grown from rash biopsies were strongly enriched for tumor antigen - specific T cells that had elevated expression of cutaneous lymphocyte antigen and chemokine receptor-6, consistent with a skin-homing phenotype. Of note, the only patient in the study with cutaneously localized disease showed a significant regression of metastatic lesions following the development of a surrounding rash. Conclusions: The evidence presented here is consistent with immunization studies in animal models and supports the concept that T cells are "imprinted" in peripheral lymph node sites to express specific ligands and chemokine receptors that allow them to migrate to skin. Furthermore, the preferential migration of the T cells to sun-exposed cutaneous sites suggests that inflammation plays a critical role in this migration. These observations suggest that further study of the effects of immunization route and inflammation on T-cell migration in humans is warranted, and could lead to vaccination approaches that would more reliably direct trafficking of activated T cells to diverse sites of metastatic disease.

Original languageEnglish (US)
Pages (from-to)5801-5808
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number19
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Grover, A., Kim, G. J., Lizée, G., Tschoi, M., Wang, G., Wunderlich, J. R., Rosenberg, S. A., Hwang, S. T., & Hwu, P. (2006). Intralymphatic dendritic cell vaccination induces tumor antigen - specific, skin-homing T lymphocytes. Clinical Cancer Research, 12(19), 5801-5808. https://doi.org/10.1158/1078-0432.CCR-05-2421