Abstract
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. 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 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. 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.
Highlights
Metastatic malignant melanoma is a devastating disease with a poor prognosis
We show here that human melanoma metastases, in general, do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule 1 (ICAM-1)(CD54) and that tumorassociated T lymphocytes in melanoma metastases accumulate primarily in the tissues immediately adjacent to, rather than within, the tumor
Immunohistochemical staining for adhesion molecules, revealed a striking absence of E-selectin, P-selectin, and ICAM-1 expression on vessels within tumor metastases and strong expression of selectin and ICAM-1 on vessels in adjacent tissue areas
Summary
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. Conclusion: 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. Trafficking of lymphocytes to specific tissues, in turn, depends on expression and interaction between specialized lymphocyte and endothelial adhesion receptors and activation pathways [23] Based on these observations, we hypothesized that the lack of benefit in tumor immunotherapy trials might reflect a defect in the process of leukocyte recruitment to melanoma metastases, preventing tumor-specific effector CTL from reaching their target and controlling tumor growth. Expression of tissuespecific homing receptors on T cells is up-regulated, or imprinted, during naive to memory transition following antigen-specific activation in tissue draining lymph nodes [28]. Naive and central memory T cells, which home to lymph nodes, characteristically express L-selectin (CD62L), chemokine receptor CCR7 (CD197), and LFA-1 (CD11a)
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