Dendritic cells (DCs) are predicted to participate in natural tumor immunity by migrating into tumors, where they acquire antigen, undergo activation, and migrate to lymph nodes to initiate a T-lymphocyte response against tumor-associated antigens. The presence of DCs using defined lineage markers and their function in human tumors has not been assessed previously. The monoclonal antibodies against CMRF-44 and CD83, which are differentiation/activation antigens on DCs, were used in immunohistological and flow cytometry studies to analyze the DC subtypes infiltrating 14 cases of human renal cell carcinoma (RCC). The functional immunocompetence of the DCs isolated from RCC was assessed by testing their ability to stimulate an allogeneic mixed leukocyte reaction. The majority of leukocytes present within the RCC were macrophages (62% +/- 14.7) or T lymphocytes (19% +/- 9.5), with CD45+ HLA-DR+ lineage-negative putative DCs accounting for less than 10% of the leukocytes present. Of these, a subset, comprising less than 1% of total leukocytes, had an activated CMRF-44+ or CD83+ DC phenotype. Activated CMRF-44+ and CD83+ DCs were more evident outside the tumor in association with T-lymphocyte clusters. The number of CMRF-44+ DCs correlated closely with the number of S-100-positive DCs. Isolation of DCs from eight RCCs was achieved, and flow cytometry studies confirmed the small proportion of activated CMRF-44+ DCs. The CMRF-44+ DCs stimulated an allogeneic mixed leukocyte reaction, but the CMRF-44- DCs (normal tissue DC precursors and other cells) failed to do so. These results suggest that RCCs recruit few DCs into the tumor substance, and the tumor environment fails to initiate the expected protective activation of DCs. These two mechanisms, amongst others, may contribute to tumor escape from immunosurveillance. In vitro loading of DCs with tumor-associated antigens may be a useful therapeutic maneuver.