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Preferential Clonogenic Deficit of CD8-positive T-Lymphocytes Infiltrating Human Solid Tumors

Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland and Division of Oncology, Policlinique Médicale Universitaire, Lausanne, Switzerland

The vast majority of tumor infiltrating lymphocytes (TIL) are either CD4⁺ or CD8⁺ T-lymphocytes. In order to examine directly the functional capabilities of the individual CD4⁺ and CD8⁺ TIL subsets we performed cell sorting of double immunofluorescence-labeled TIL recovered from 15 biopsies by enzyme digestion. These CD4⁺ and CD8⁺ TIL subsets were compared with similar subsets of T-lymphocytes from peripheral blood of normal subjects. Both CD4⁺ and CD8⁺ TIL showed a reduced clonogenicity as assessed quantitatively by limiting dilution analysis in a microculture system which allows every normal T-lymphocyte to undergo clonal expansion. The reduced clonogenic potential was unequally distributed among the CD4⁺ and CD8⁺ subsets with the CD8⁺ TIL showing a significant reduction of the frequency of proliferating T-lymphocyte precursors compared to the CD4⁺ TIL (with a median of 1/50 proliferating T-lymphocytes in CD8⁺ TIL versus a median of 1/11 in CD4⁺ TIL). The reduced response of CD8⁺ TIL was not caused by suppressor cells, lack of surface expression of CD2 and CD3 antigens nor of the , ß T-cell receptor, nor by an accumulation of CD8⁺ cells of large granular lymphocyte morphology. Using low density cultures, the highly purified CD4⁺ and CD8⁺ TIL were stimulated either via the T-cell receptor or the CD2-mediated antigen-independent pathway of activation. Whereas CD8⁺ TIL did not respond to either stimulus the CD4⁺ TIL showed evidence of responder and nonresponder groups. In addition, we show that the deficient response obtained by triggering CD4⁺ TIL via the TCR can be restored by activation of the antigen-independent pathway. Finally, a total of 94 clones from four different TIL samples were obtained by limiting dilution and examined for their respective helper and cytolytic capabilities: 57% of the CD4⁺ TIL clones were able to produce interleukin 2 and 93% of the CD8⁺ TIL clones demonstrated cytolytic activity mediated by the T-cell receptor complex, indicating that the functional potential of proliferating TIL is intact.

¹ Recipient of a training grant from the Deutsche Forschungsgemeinschaft (D. F. G.).

² Recipient of a training grant from the Swiss Cancer League.

³ To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, Laboratoire d'oncologie, CHUV-BH 19-602, 1011 Lausanne, Switzerland.

Received 5/10/88. Revised 8/29/88. Accepted 9/21/88.