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

Abstract

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. T-TIL 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 IL2Rβ as the percentage of T-cells expressing CD3 and IL2Rβ were comparable in both T-TIL and peripheral blood T-cells obtained from the same patient. In contrast to the lack of proliferative activity, stimulation of T-TIL or peripheral blood lymphocytes with phytohemagglutinin or anti-CD3 resulted in comparable levels of both IL2 and γ-interferon mRNA and protein expression. While levels of IL2Rα were low in unstimulated T-TIL and peripheral blood lymphocytes, anti-CD3 antibody or IL2 were capable of inducing surface expression of this protein in both cell populations. IL2Rα mRNA levels were comparable in T-cells from the tumor and peripheral blood although in some experiments both the percentage of IL2Rα-positive cells and the density of surface expression per cell were reduced in T-TIL. This reduced IL2Rα expression on T-TIL was not responsible for the proliferative unresponsiveness since T-TIL that expressed both IL2Rα and/or IL2Rβ still failed to respond to high doses of IL2. Thus T-TIL display a selective loss of response to at least two well defined 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 IL2 in terms of IL2 and γ-interferon or IL2Rα expression, respectively. The fact that proliferative unresponsiveness exists even though T-TIL can produce IL2 and express IL2Rα/β 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.