T-Cells Infiltrating Renal Cell Carcinoma Display a Poor Proliferative Response Even Though They Can Produce Interleukin 2 and Express Interleukin 2 Receptors1

The fact that progressing tumors contain a significant infiltrate of T-cells brings into question the competency of the infiltrating T-lymphocytes (T-TIL). We have examined the role of the T-cell receptor/CD3 complex and/or the interkeukin 2 receptor (IL2R) in responsiveness of T-cells that infiltrate human renal cell carcinoma. IIII, display a poor proliferative response to interleukin 2 (IL2) alone, IL2 in combination with antibody to CD3, or mitogen stimulation. The proliferative unresponsiveness was not related to low expression of CD3 or IL2Rßas the per centage of T-cells expressing CD3 and IL2R0 were comparable in both l-'l II. and peripheral blood T-cells obtained from the same patient. In contrast to the lack of proliferative activity, stimulation of T-TIL or pe ripheral blood lymphocytes with phytohemagglutinin or anti-CD3 re sulted in comparable levels of both IL2 and -y-interferon niRNA and protein expression. While levels of IL2Ra were low in unstimulated T-TIL and peripheral blood lymphocytes, anti-CD3 antibody or IL2 were capa ble of inducing surface expression of this protein in both cell populations. IL2Ra mRNA levels were comparable in T-cells from the tumor and peripheral blood although in some experiments both the percentage of IL2Ra-positive cells and the density of surface expression per cell were reduced in T-TIL. This reduced IL2Ra expression on T-TIL was not responsible for the proliferative unresponsiveness since T-TIL that ex pressed both IL2Ra and/or IL2Rßstill failed to respond to high doses of 11.2. Thus T-TIL display a selective loss of response to at least two well denned extracellular stimuli. While T-TIL exhibit a poor proliferative response regardless of the form of stimulation these cells remain sensitive to both anti-CD3 and 11.2 in terms of IL2 and -y-interferon or II .2R<» expression, respectively. The fact that proliferative unresponsiveness exists even though T-TIL can produce II .2 and express II JR..//1 suggests that T-TIL have a selective loss of a common intracellular signaling pathway which is requisite to proliferation but not other aspects of response to antigenic stimulation.