Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer

Abstract

Purpose: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as aT-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored. Experimental Design: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killerT cells (iNKT), and CD4 + CD25 + regulatory-typeTcells. Results: The frequency of both circulating myeloid DC1and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4À iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4 + CD25 + T cells, including CD4 + Foxp3 + T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4 + CD25 + T cells in response to IL-2. Functionally, patient CD25 + T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25 + Tcells and mostly failed toTh2 polarize iNKT. Conclusions: Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.

Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells

“…Importantly, CD1d was predominantly expressed by mDC1 (Fig. 1B), confirming earlier reports (23,25), and expression levels were found to be comparable in healthy controls and cancer patients ( p ϭ 0.65). As the CD1d Ag-presenting molecule is required for the presentation of glycolipid Ag to iNKT cells, mDC1 were selected for additional experiments.…”

“…Induction of IFN-␥ from iNKT and IL-12 from DC can act as a "positive feedback loop" and drive Th1 responses (1, 2, 18 -22). We recently showed that the circulating human CD1d ϩ DC subset, mDC1, responds like iNKT to high-dose IL-2 treatment, whereas CD4 ϩ CD25 ϩ regulatory type T cells behaved reciprocally (23). We hypothesized that the reported quantitative and/or qualitative differences in the circulating DC of cancer patients could contribute to the observed defects in iNKT cells and we therefore compared interactions between iNKT cells and CD1d-expressing circulating DC from healthy donors and patients with advanced cancer.…”

Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer

“…17,[33][34][35] Analysis of patients in the present trial who received NMA alone revealed that the number of IL-2 doses was strongly associated with the total number of CD4 ϩ Tregs, but only moderately to weakly associated with the percentages of CD4 ϩ Tregs in the peripheral blood at week 1 ( Figure 5A first column). The number of IL-2 doses appeared to be weakly to moderately associated with peripheral CD4 ϩ Treg reconstitution in the 2-Gy trial, but were not associated with CD4 ϩ Treg reconstitution in the 12-Gy trial, perhaps as a consequence of the significant depletion of peripheral CD4 ϩ Tregs observed in patients receiving TBI ( Figure 5A).…”

Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

“…Preferential activation of CD8 ϩ T cells or Tregs by IL-2 is not strictly dependent on the dose of IL-2 (ie, lower and higher doses of IL-2 can activate both) but rather depends on the preactivation status of CD8 ϩ cells because resting peripheral T cells do not express the high-affinity trimeric IL-2R until activated by specific antigens. [117][118][119][120] When CD8 ϩ CTLs are already active and express CD25, IL-2 may preferentially augment CTLmediated responses rather than Treg-mediated responses and thus can exacerbate GVHD. However, in vivo models suggests that a greater level of local IL-2 in conditions such as inflammation may promote the induction of nTreg cell function and subsequently inhibit clonal expansion and function of Teffs.…”