T-cell distribution and adhesion receptor expression in metastatic melanoma.
OBJECTIVE
Metastatic malignant melanoma is a devastating disease with a poor prognosis. Recent therapeutic trials have focused on immunotherapy to induce development of endogenous antitumor immune responses. To date, such protocols have shown success in activation of tumor-specific CTL but no overall improvement in survival. To kill tumor, antigen-specific CTL must efficiently target and enter tumor tissue. The purpose of this study was to examine the pathway of leukocyte migration to metastatic melanoma.


METHODS
Peripheral blood and metastatic melanoma tissues (n = 65) were evaluated for expression of adhesion molecules using immunohistochemistry of tumor sections and flow cytometry of tumor-associated and peripheral blood CTL and compared with healthy controls. CTL expressing T-cell receptors for the melanoma antigen MART-1 were identified in a subset of samples by reactivity with HLA-A2 tetramers loaded with MART-1 peptide.


RESULTS
Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. Strong adhesion receptor expression was noted on vessels within adjacent tissue. Tumor-associated T lymphocytes accumulate preferentially in these adjacent areas and are not enriched for skin- or lymph node-homing receptor phenotype.


CONCLUSIONS
Expression of leukocyte homing receptors is dysregulated on the vasculature of metastatic melanoma. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.
Weishaupt
Carsten
C
Department of Dermatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Munoz
Karla N
KN
Buzney
Elizabeth
E
Kupper
Thomas S
TS
Fuhlbrigge
Robert C
RC
D000951:Antigens, Neoplasm / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002448:Cell Adhesion; D019040:E-Selectin / Q000032:analysis / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000737:chemistry / Q000276:immunology / Q000556:secondary*; D009363:Neoplasm Proteins / Q000032:analysis; D019007:P-Selectin / Q000032:analysis / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D016201:Receptors, Lymphocyte Homing / Q000032:analysis / Q000378:metabolism*; D012878:Skin Neoplasms / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D019040:E-Selectin; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D019007:P-Selectin; D011948:Receptors, Antigen, T-Cell; D016201:Receptors, Lymphocyte Homing; D018799:Intercellular Adhesion Molecule-1