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


METHODS
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.
Grover
Amelia
A
Surgery Branch and Dermatology Branch, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Kim
Grace J
GJ
Lizée
Gregory
G
Tschoi
Mary
M
Wang
Gang
G
Wunderlich
John R
JR
Rosenberg
Steven A
SA
Hwang
Sam T
ST
Hwu
Patrick
P
D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen