Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8(+) T cells in melanoma patients receiving interleukin 12

Systemic effects on T-cell-mediated antitumor immunity, on expression of T- cell adhesion/homing receptors, and on the promotion of T-cell infiltration of neoplastic tissue may represent key steps for the efficacy of immunolog ical therapies of cancer. In this study, we investigated whether these proc esses ran be promoted by s.c. administration of low-dose (0.5 mu g/kg) reco mbinant human interleukin-12 (rHuIL-12) to metastatic melanoma patients. A striking burst of IILA-restricted CTL precursors (CTLp) directed to autolog ous tumor was documented in peripheral blood by a high-efficiency limiting dilution analysis technique within a few days after rHuIL-12 injection. A s imilar burst In peripheral CTLp frequency was observed even when looking at response to a single tumor-derived peptide, as documented by an increase i n Melan-A/Mart-1(27-35)-specific CTLp in two HLA-A*0201(+) patients by limi ting dilution analysis and by staining peripheral blood lymphocytes (PBLs) with HLA-A*0201-melanoma antigen-A/melanoma antigen recognized by T cells ( Melan-A/Mart)-1 tetrameric complexes. The CTLp burst was associated, in PBL s, with enhanced expression of T-cell adhesion/homing receptors CD11a/CD18, CD49d, CD44, and with increased proportion of cutaneous lymphocyte antigen (CLA)-positive T cells. This was matched by a marked increase, in serum, o f soluble forms of the endothelial cell adhesion molecules E-selectin, vasc ular cell adhesion molecules (VCAM)-1 and intercellular adhesion molecules (ICAM)-1, Infiltration of neoplastic tissue by CD8(+) T cells with a memory and cytolytic phenotype was found by immunohistochemistry in eight of eigh t posttreatment metastatic lesions but not in five of Five pretreatment met astatic lesions from three patients. Increased tumor necrosis and/or fibros is were also found in several posttherapy lesions of two of three patients in comparison with pretherapy metastases, These results provide the first e vidence that rHuIL-12 can boost the frequency of circulating antitumor CTLp in tumor patients, enhances expression of ligand receptor pairs contributi ng to the lymphocyte function-associated antigen-1/ICAM-1, very late antige n-4/VCAM-1, and CLA/E-selectin adhesion pathways, and promotes infiltration of neoplastic lesions by CD8(+) memory T cells in a clinical setting.