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Frequent Down-Regulation of Major Histocompatibility Class I Antigen Expression on Individual Micrometastatic Carcinoma Cells¹

Institut für Immunologie [K. P., D. K., G. R.], I. Frauenklinik der Universität München [G. Scha., T. G.], Institut für Pathologie [B. W.], and Chirurgische Klinik im Klinikum Grosshadern, Ludwig-Maximilians-Universität [I. F.], W-8000 Munich 2, and Medizinische Klinik II [G. Schl.) and Pathologisches Institut im Zentralklinikum Augsburg [R. B.], W-8900 Augsburg, Germany

An astoundingly high frequency of micrometastatic cells have been found in bone marrow aspirates of patients with colon carcinomas (G. Schlimok et al., J. Clin. Oncol., 8:831–837, 1990), although these tumors very rarely metastasize to the skeleton. This observation has raised questions about the malignant potential of such cells. In a first attempt to characterize this potential, we have assessed the expression of major histocompatibility complex (MHC) class I antigens on bone marrow micrometastases, inasmuch as down-regulation of these molecules is a potential mechanism to escape from MHC class I-restricted lysis by cytotoxic T-cells. The two groups of cancer patients compared were those with tumors known to rarely (stomach and colon cancer) or frequently (breast cancer) manifest skeleton metastases. Bone marrow aspirates taken from these patients were probed for individual disseminated tumor cells using the immunoalkaline phosphatase technique with monoclonal antibody CK2 to the epithelial differentiation antigen cytokeratin 18 (CK-18), as described previously (G. Schlimok et al., Proc. Natl. Acad. Sci. USA, 84: 8672–8676, 1987). Specimens containing CK18-positive cells were colabeled with monoclonal antibody W6/32 directed to a framework (or nonpolymorphic) antigenic determinant of MHC class I heavy chains associated with ß₂-microglobulin. W6/32-positive CK-18-positive cells could be detected in 25 of 54 patients (46.3%) with significantly higher incidences in 26 breast cancer patients (61.9%) as compared to 28 patients with carcinomas of the stomach and colon (27.3 and 29.4%). Independent from the origin of the primary carcinoma, the incidence of W6/32-negative CK18-positive cells was positively correlated to both the differentiation grade of the primary tumor (P < 0.05) and appeared to be linked to the occurrence of regional lymph node metastases (statistically not significant) determined by conventional histological examination. The present results demonstrate for the first time that down-regulation of MHC expression on individual micrometastatic cells correlates to the differential pattern of metastasis obtained by comparing breast and gastrointestinal carcinomas. This finding together with the suggestive link to clinical risk factors supports the significance of reduced MHC class I expression for the survival of residual metastatic cells which is a major determinant of prognosis for patients with solid tumors.

¹ This work was supported by grants from the Dr. Mildred Scheel Stiftung/Deutsche Krebshilfe, Bonn; the Wilhelm-Sander-Stiftung, Neuburg/Donau; and the W. Vaillant-Stiftung, Munich, Germany.

² To whom requests for reprints should be addressed, at Institut für Immunologie der LMU München, Goethestrasse 31, W-8000 Munich 2, Germany.

Received 4/ 5/91. Accepted 6/19/91.

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