PREDOMINANCE OF A TYPE-2 INTRATUMORAL IMMUNE-RESPONSE IN FRESH TUMOR-INFILTRATING LYMPHOCYTES FROM HUMAN GLIOMAS

Increasing evidence suggests the existence of polarized human T cell r esponses described as Th1-type (promoting cell-mediated immunity) and Th2-type (promoting humoral immunity), characterized by a dominant pro duction of either interferon-gamma (IFN-gamma) or IL-4, respectively. Little is known about the intratumoural activation of infiltrating lym phocytes (TIL) in human gliomas. Therefore, we assessed fresh TIL at c ellular and molecular levels to find out if they were activated and po larized into a type 1 or 2 immune response. Flow cytometry analysis of TIL revealed that the major subset was made of T lymphocytes. Double labelling with alpha-CD3 and adhesion/ activation markers revealed T c ell subsets expressing CD39a, CD49b, CD54, and CD15, some of which wer e almost absent in autologous T peripheral blood lymphocytes (T-PBL). Furthermore, the proportions of T-TIL expressing CD56, CD65, or CD25 w ere several-fold higher than in T-PBL. Intratumoural functional activa tion of TIL was tested by semiquantitative assessment in relative unit s (RU) of lymphokine gene activation with mRNA reverse transcriptase-p olymerase chain reaction (RT-PCR). All TIL populations except one sign ificantly expressed IL-4 1 to 2 logs of RU above healthy PBL baseline. Similarly, all patients expressed granulocyte-macrophage colony-stimu lating factor (GM-CSF) in a range comparable to IL-4. However, most TI L populations did not express IFN-gamma, IL-2, and tumour necrosis fac tor-beta (TNF-beta) at higher levels than healthy normal PBL. The incr eased proportion of T cells expressing activation markers and the cons istent detection of significant IL-4 and GM-CSF lymphokine gene activa tion in TIL populations suggested a predominant type 2 intratumoural i mmune response that does not promote cell-mediated tumouricidal activi ty and may contribute to the inefficiency of the antiglioma immune res ponse.